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SS 2017: The resistance march
Antimicrobial resistance has been an ongoing issue since the discovery of early antimicrobial treatments. Resistance first emerged in the early 1900s in Neisseria gonorrhoeae and has since developed to nearly all classes of antimicrobials used to treat it. Resistance is now widespread globally to previously effective drugs. New treatment guidelines must consider emerging resistance patterns and combine antimicrobials to preserve effectiveness. Ongoing surveillance is also needed to monitor resistance trends and ensure optimal treatment strategies.
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SS 2017: The resistance march
- 1. Resistance Dr. Phillip Hay Isit time to abandon 1G azithromycin?
- 2. Antimicrobial Resistance • Trichomonasvaginalis (Donne 1836) • Neisseria gonorrhoeae (Neisser 1879) • Treponema pallidum (Hoffmann and Schaudinn 1905) • Candida albicans (Berkhout 1923) • Herpes simplex (Gruter, 1924) • Chlamydia trachomatis (1957) • LGV(Findlay 1933, Wang & Grayston, 1970) • Mycoplasma genitalium (Tully & Taylor-Robinson 1981) • HIV (Montagnier 1983)
- 3.
- 4. Impact of agenetic variant of Chlamydia trachomatis on national detection rates in Sweden Eurosurveillance, Volume 11, Issue 49, 07 December 2006
- 5. Impact of agenetic variant of Chlamydia trachomatis on national detection rates in Sweden Eurosurveillance, Volume 11, Issue 49, 07 December 2006
- 6. Cryptic Plasmid targetfor NAATs • Abbott m2000, Cobas Amplicor/TaqMan48 • 5–10 copies of this plasmid per cell • Genes not essential for survival • Plasmid free strains of C trachomatis were reported in the early 1990s • If a single test system dominates a market too much, the appearance of a mutant will be more difficult to observe and the lack of alternative detection systems will make laboratory diagnostics even more vulnerable.
- 7. Heterotypic resistance inChlamydia • Conventional antimicrobial resistance has only rarely been observed with C. trachomatis clinical isolates. • At high infection loads, in vitro persistence can often be demonstrated to antimicrobials—heterotypic resistance. • The subsequently recovered isolates do not possess antimicrobial resistance at low loads • 8% ( 95% CI 5% to 11%) failure rate using recommended treatment regimens for uncomplicated genital C trachomatis infection in 289 women who had not subsequently been sexually active. Golden et al N Engl J Med 2005;352:676–85
- 8. Antimicrobial resistance arisesas the result of the perpetual evolutionary struggle between hosts and pathogens, and as we aimed to demonstrate, various genetic changes represent the main mechanism in pathogenic bacteria (113). In C. trachomatis such events may involve mutations in conserved regions of 23S rRNA genes, horizontal gene transfer, nucleotide substitution and a myriad of other significant mechanisms. For one small, intracellular bacterial species, it is a rather rich repertoire of mechanisms responsible for developing resistance to antimicrobial agents (although its occurrence is still mostly confined to the in vitro setting).
- 12. RCT: 1G Azithrov 7/7 doxy for NGU • 398 enrolled: 197 azithromycin, 201 doxycycline. • Thirty-six (18%) and 42 (21%) men in these 2 groups, respectively, were infected with M. genitalium. • initial follow-up visit, M. genitalium found in: • 3 (13%) of 23 azithromycin • 17 (55%) of 31 doxycycline-treated men • Of 15 persistently infected men who were clinically cured at the early initial follow-up visit, 7 (47%) experienced clinical relapse over the subsequent 2–6 weeks. Mena LA et al Clinical Infectious Diseases 2009; 48:1649–54
- 13.
- 14. Mycoplasma genitalium • RCTin USA • Azithromycin failed to clear in 3/23 (17%) • Doxycycline failed to clear in 17/21 (55%) • In Denmark • 5/7 men with persistent urethritis acquired macrolide resistance after 1G azithromycin • 500 mg on day 1 followed by 250 mg daily on days 2–5 cured >95% Mena LA et al Clinical Infectious Diseases 2009; 48:1649–54 Jensen JS et al Clin Infect Dis 2008;47: 1546-1553 Jensen JS Clinical Infectious Diseases 2009; 48:1655–6
- 15. Sleepwalking into M.genitalium Resistance • As common as CT in NGU • No routine diagnostic test • Doxycycline – 50% failure • Azithro 1G – 20% fail with resistance emerging • Extended azithro 10% fail • Moxifloxacin resitance emerging • Pristinamycin resistance reported
- 16. Syphilis • No penicillinresistance to date, but some treatment failures • 2002 Azithromycin resistance San Francisco • 23S ribosomal RNA mutation • Dublin 88%, San Francisco 22%, Seattle13%
- 18. Trichomonas vaginalis • Untreatableif metronidazole resistant • Desensitisation if allergic
- 20. • Sulphonamides 1935cure > 80-90% • 1950 > 90% isolates resistant • Penicillins • 1930 Cecil Paine: crude extract from Penicillium notatum to treat ophthalmia neonatorum • 1943 penicillin for urethritis, 45 mg > 90% cure • Rising MICs from chromosomal mutations • 1976 PPNG
- 23. • Tetracyclines • Forpenicillin allergic in 1940s, post-gonococcal urethritis • Stepwise chromosomal mutations • 1985 Plasmid-mediated tetracycline-resistant N gonorrhoeae (TRNG) • Aminoglycosides • Spectinomycin specifically developed 1960s • Ineffective for pharynx • US military Korea in 1981 • after 4 years, 8.2% treatment failure rate
- 24. • Macrolides • Erythromycinpoor activity • Azithromycin 2G – poor tolerability • Resistance from modifying 50S ribosomal subunit or increased efflux • Azithromycin resistance in Latin America post 1995 • Clusters in USA and Europe more recently
- 25. • Quinolones • 1980s250 mg ciprofloxacin – good pharyngeal penetration • Dose raised to 500 mg • Chromosomal resistance 1991 MSM Hawaii • Mid 1990s abandoned in Asia – Pacific • USA and Europe highly prevalent in MSM
- 26. Historical perspective onantimicrobial resistance in the United Workowski K A et al. Ann Intern Med 2008;148:606-613 ©2008 by American College of Physicians
- 27. Cefixime decreased susceptibility (MIC≥0.125mg/l)and (MIC≥0.25mg/l), 2004 -2009 Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)
- 28. Ciprofloxacin (MIC≥1mg/l) resistanceby gender and sexual orientation, 2000-2009 Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)
- 30. Knapp JS, HookEW 3rd. Prevalence and persistence of Neisseria cinerea and other Neisseria spp. in adults. J Clin Microbiol. 1988 May;26(5):896-900
- 31. Pharmacodynamic Principles • Criticalparameter • Β-Lactams: Proportion of dosage when drug level> MIC • Aminoglycosides: Ratio of peak level to MIC • Quinolones: Ratio of AUC to MIC • Target parameter • Value of critical parameter predicting success • Monte Carlo Simulation • Statistical method for predicting population variation around the target parameter
- 32. Multi-dose regimens • Ceftriaxone1G followed by cefixime 400mg od for two days • Maintains free drug > MIC for 40% treatment period even if MIC to both drugs is 0.25 mg/L • Dosages achieve lower 95% confidence intervals in the simulation
- 35. Transformation • GC isnaturally competent for transformation and • Interspecies and intraspecies recombination has been widely reported at numerous loci
- 39.
- 40. In the pharynx,gonorrhoea: • Commonly occurs in risk groups without concurrent anogenital infection; • Transmission is efficient by both fellatio and insertive oro-anal contact; • Diagnosis by culture is insensitive and should be replaced by NAATs; culture remains important for surveillance of antimicrobial resistance; • Isolates with multiple antibiotic resistance can emerge; • Treatment failure is more likely, and a test of cure is essential.
- 41. • 4 dosesof azithromycin over 9 months • Resistance in nasopharyngeal Pneumococci increased from 3.6% to 46.9% • Carriage rates 69% - 78%
- 42. Conclusions • Increasing resistanceappears inevitable • GC – throat • We don’t know when it is there • Culture is insensitive • NAAT more sensitive but ? How much • NAAT specificity may be poor • No resistance data with NAAT • Test of cure by NAAT • Combine Fosfomycin with ceftriaxone? • Combine ceftriaxone with extended cefixime course? • Gentamycin • New agents
- 43. Other Infections • M.genitalium • Safest to use doxycycline first line for NGU • Extended course azithromycin for treatment failures • Chlamydia • Clinical vigilance for treatment failures • Test regimens with longer duration • Sentinel surveillance for resistance • Syphilis • Avoid macrolides • BV
- 44. Antimicrobial Resistance • Trichomonasvaginalis (Donne 1836) • Neisseria gonorrhoeae (Neisser 1879) • Treponema pallidum (Hoffmann and Schaudinn 1905) • Candida albicans (Berkhout 1923) • Herpes simplex (Gruter, 1924) • Chlamydia trachomatis (1957) • LGV(Findlay 1933, Wang & Grayston, 1970) • Mycoplasma genitalium (Tully & Taylor-Robinson 1981) • HIV (Montagnier 1983)
- 56. Historical perspective onantimicrobial resistance in the United States.QRNG = quinolone- resistant Neisseria gonorrhoeae; MSM = men who have sex with men. Workowski K A et al. Ann Intern Med 2008;148:606-613 ©2008 by American College of Physicians
- 57.
- 64. 0 0.5 1 1.5 2 2.5 3 3.5 2004 2005 20062007 2008 %ofpatients MSM Heterosexual Males Females Cefixime decreased susceptibility (>=0.25mg/l) by sexual orientation in England and Wales GRASP - The Gonococcal Resistance to Antimicrobials Surveillance Programme; sentinel data from 24 laboratories and 26 GUM clinics
- 65. 0 5 10 15 20 25 30 35 2000 2001 20022003 2004 2005 2006 2007 2008 MSM Heterosexual Males Females GRASP - The Gonococcal Resistance to Antimicrobials Surveillance Programme; sentinel data from 24 laboratories and 26 GUM clinics CMRNG resistance* by sexual orientation in England and Wales * ß-lactamase negative, penicillin >=1mg/l, and tetracycline between 2-8 mg/l
- 66. 0 10 20 30 40 50 60 70 80 90 100 2004 2005 20062007 2008 %patientsprescribedantimicrobial 0 5 10 15 20 25 30 %resistanceordecreasedsusceptibility Fluoroquinolones Cephalosporins % Ciprofloxacin resistance (>=1mg/l) % Cefixime decreased susceptibility (>=0.25mg/l) Antimicrobial prescribing practice in England and Wales GRASP - The Gonococcal Resistance to Antimicrobials Surveillance Programme; sentinel data from 24 laboratories and 26 GUM clinics
- 67. 0 5 10 15 20 25 30 35 40 45 50 2004 2005 20062007 2008 %resistant Asian Black African Black Caribbean White GRASP - The Gonococcal Resistance to Antimicrobials Surveillance Programme; sentinel data from 24 laboratories and 26 GUM clinics Prevalence of ciprofloxacin resistant (>=1mg/l) gonorrhoea in England and Wales, by ethnic group:
Editor's Notes
- #2 http://www.ilovewavs.com/Effects/Music/Sound%20Effect%20-%20Funeral%20March.wav
- #6 This trend is even more visible when the first half of 2006 is compared with the same period in 2005. A 10% decline in number of chlamydia cases diagnosed with Roche or Abbott tests can be seen, compared with a 1% increase in cases detected with the BectonDickinson test. This could be caused by a nationwide distribution of a genetic variant of Chlamydia trachomatis being undiagnosed.
- #7 The first description reported that the new variant constituted 13% of all detected chlamydia infections (from mid-September to October 2006) in the county of Halland (south west of Sweden). It soon became apparent that the proportion was higher and that the new variant had spread widely in Sweden. 2– 4 We now know that in the counties that have used the Abbott or Roche test systems during the past year or so the new variant accounts for 20% to 65% of all detected chlamydia cases. In local areas, as many as 78% of all cases have been found to have the mutation (Britta Loré, personal communication).
- #10 Azithromycin and doxycycline were used for the sus- ceptibility assay using the cell culture technique for the 2l C. trachomatis isolates. Thirteen isolates (61.90/o) were found to be susceptible to these drugs and have shown MIC values equal to those of the standard isolate, i.e. <0.125 and <0.25 pglml for azithromycin and doxycy- cline, respectively. However, 8 isolates (38%) showed a modified antibiotic susceptibility profile. The suscepti- bility profile of these isolates is presented in table 1. The MIC values for these 8 isolates vary from 0.12 to 8 pg/ml for azithromycin and from 0.025 to 8.0 pglml for doxy- cycline. Six isolates obtained from the recurrently infect- ed patients showed a decreased susceptibility to both drugs (table 1), while 3 isolates which were also obtained from the recurrently infected patients showed a suscepti- bility comparable to that of the control.
- #11 Chlamydial Persistence: beyond the Biphasic Paradigm C. trachomatis serovar L2 mutants isolated from cell culture after several rounds of exposure to various fluoroquinolones consistently showed a point mutation in gyrA (encoding DNA gyrase subunit A), suggesting that DNA gyrase is the primary target of these antibiotics (29). However, a recent study described C. trachomatis isolates associated with treatment failure that were resistant to multiple drugs with diverse molecular targets (doxycycline, azithromycin, and ofloxacin at concentrations above 4 ug/ml) (115). This indicated the presence of a more global resistance mechanism such as the induction of a persistent phenotype that is refractory to multiple antibiotics, for example, through membrane alterations that affect drug intake. In some cases, the explanation for resistance could be more complex; certain genotypes could confer antibiotic resistance by encouraging development of the persistent phenotype. Such a scenario seems to occur in tetracycline-resistant porcine C. trachomatis strains, which produced large aberrant RB in response to the antibiotic at 2 ug/ml (66). Could the gyrA mutations that developed in cell culture in response to fluoroquinolone exposure (29) also favour the formation of a persistent phenotype, since alterations to DNA gyrase could inhibit RB-to-EB differentiation?
- #13 Background. Several uncontrolled observational studies have suggested that the tetracycline class of antibiotics may not be effective in treating Mycoplasma genitalium infection. The present study compared the efficacy of 1 g of azithromycin given as a single dose with that of 100 mg of doxycycline given twice a day for 7 days in eliminating M. genitalium infection. Methods. Men with signs or symptoms of urethral disease who were attending a New Orleans sexually trans- mitted disease clinic and who met clinical criteria for nongonococcal urethritis were enrolled in the study. They were randomized to receive either doxycycline (100 mg orally twice a day for 7 days) or azithromycin (1 g orally as a single dose). All participants were asked to return for a follow-up visit 10–17 days after enrollment. M. genitalium–positive men at enrollment were invited to return for a second follow-up visit between 31 and 41 days after enrollment. Results. Of the 398 men who enrolled, 197 were randomized to receive azithromycin, and 201 were randomized o receive doxycycline. Thirty-six (18%) and 42 (21%) men in these 2 groups, respectively, were infected with M. genitalium. At the early initial follow-up visit, 3 (13%) of 23 azithromycin-treated men were M. genitalium positive, compared with 17 (55%) of 31 doxycycline-treated men (Pp.002). Of 15 persistently infected men who were clinically cured at the early initial follow-up visit, 7 (47%) experienced clinical relapse over the subsequent 2–6 weeks. Conclusions. A single 1-g dose of azithromycin is more effective than multidose doxycycline for the treatment of M. genitalium–associated urethritis in men.M. genitalium may be an important cause of recurrent nongonococcal urethritis after administration of the treatment regimens currently recommended by the Centers for Disease Control and Prevention.
- #15 A Randomized Comparison of Azithromycin and Doxycycline for the Treatment of Mycoplasma genitalium–Positive Urethritis in Men Leandro A. Mena,1 Tomasz F. Mroczkowski,2 Malanda Nsuami,2 and David H. Martin2 1University of Mississippi School of Medicine, Jackson; and 2Louisiana State University School of Medicine, New Orleans Clinical Infectious Diseases 2009; 48:1649–54 (See the editorial commentary by Jensen on pages 1655–6) Background. Several uncontrolled observational studies have suggested that the tetracycline class of antibiotics may not be effective in treating Mycoplasma genitalium infection. The present study compared the efficacy of 1 g of azithromycin given as a single dose with that of 100 mg of doxycycline given twice a day for 7 days in eliminating M. genitalium infection. Methods. Men with signs or symptoms of urethral disease who were attending a New Orleans sexually transmitted disease clinic and who met clinical criteria for nongonococcal urethritis were enrolled in the study. They were randomized to receive either doxycycline (100 mg orally twice a day for 7 days) or azithromycin (1 g orally as a single dose). All participants were asked to return for a follow-up visit 10–17 days after enrollment. M. genitalium–positive men at enrollment were invited to return for a second follow-up visit between 31 and 41 days after enrollment. Results. Of the 398 men who enrolled, 197 were randomized to receive azithromycin, and 201 were randomized to receive doxycycline. Thirty-six (18%) and 42 (21%) men in these 2 groups, respectively, were infected with M. genitalium. At the early initial follow-up visit, 3 (13%) of 23 azithromycin-treated men were M. genitalium positive, compared with 17 (55%) of 31 doxycycline-treated men (Pp.002). Of 15 persistently infected men who were clinically cured at the early initial follow-up visit, 7 (47%) experienced clinical relapse over the subsequent 2–6 weeks. Conclusions. A single 1-g dose of azithromycin is more effective than multidose doxycycline for the treatment of M. genitalium–associated urethritis in men. M. genitalium may be an important cause of recurrent nongonococcal urethritis after administration of the treatment regimens currently recommended by the Centers for Disease Control and Prevention. Single-Dose Azithromycin for M genitalium Urethritis- Best but Not Good Enough Jensen JS Clinical Infectious Diseases 2009; 48:1655–6 Azithromycin Treatment Failure in Mycoplasma genitalium–Positive Patients with Nongonococcal Urethritis Is Associated with Induced Macrolide Resistance Jørgen S. Jensen,1 Catriona S. Bradshaw,2,3 Sepehr N. Tabrizi,4,5 Christopher K. Fairley,3,6 and Ryoichi Hamasuna7 Clinical Infectious Diseases 2008;47:1546–1553 Background.Mycoplasma genitalium is a common cause of nongonococcal urethritis. Treatment trials have shown that doxycycline is inefficient, whereas a 5‐day course of azithromycin eradicates the bacterium from 95% of infected men. The aim of the study was to establish the reason for the occasional treatment failures. Methods.Seven M. genitalium strains isolated from men who experienced azithromycin treatment failure were tested for in vitro susceptibility to macrolides with use of a cell culture–based method. The genetic basis for the drug resistance was established by sequencing parts of the 23S ribosomal RNA gene and the genes encoding the L4 and L22 proteins. Nine sets of specimens obtained before and after treatment from patients who experienced azithromycin treatment failure were examined with use of sequencing of polymerase chain reaction products. Results.The 7 strains that were isolated from patients who experienced treatment failure with azithromycin had minimum inhibitory concentrations >8 μg/mL for azithromycin and erythromycin. Three different mutations at positions 2058 and 2059 (Escherichia colinumbering) in region V of the 23S rRNA gene were found. Of the 9 patients with specimens obtained before and after treatment, only 2 had an initial specimen in which the mutation was present, indicating that drug resistance was induced as the result of an inappropriate dosage of azithromycin. Conclusion.Development of macrolide resistance was shown to correlate with subsequent azithromycin treatment failure. The genetic basis for the drug resistance was shown to be mutations in region V of the 23S rRNA gene, which is well described in other Mollicutes. These findings raise concern about the use of single‐dose azithromycin treatment of nongonococcal urethritis of unknown etiology. Azithromycin Treatment Failure in Mycoplasma genitalium–Positive Patients with Nongonococcal Urethritis Is Associated with Induced Macrolide Resistance
- #16 Background. Several uncontrolled observational studies have suggested that the tetracycline class of antibiotics may not be effective in treating Mycoplasma genitalium infection. The present study compared the efficacy of 1 g of azithromycin given as a single dose with that of 100 mg of doxycycline given twice a day for 7 days in eliminating M. genitalium infection. Methods. Men with signs or symptoms of urethral disease who were attending a New Orleans sexually trans- mitted disease clinic and who met clinical criteria for nongonococcal urethritis were enrolled in the study. They were randomized to receive either doxycycline (100 mg orally twice a day for 7 days) or azithromycin (1 g orally as a single dose). All participants were asked to return for a follow-up visit 10–17 days after enrollment. M. genitalium–positive men at enrollment were invited to return for a second follow-up visit between 31 and 41 days after enrollment. Results. Of the 398 men who enrolled, 197 were randomized to receive azithromycin, and 201 were randomized o receive doxycycline. Thirty-six (18%) and 42 (21%) men in these 2 groups, respectively, were infected with M. genitalium. At the early initial follow-up visit, 3 (13%) of 23 azithromycin-treated men were M. genitalium positive, compared with 17 (55%) of 31 doxycycline-treated men (Pp.002). Of 15 persistently infected men who were clinically cured at the early initial follow-up visit, 7 (47%) experienced clinical relapse over the subsequent 2–6 weeks. Conclusions. A single 1-g dose of azithromycin is more effective than multidose doxycycline for the treatment of M. genitalium–associated urethritis in men.M. genitalium may be an important cause of recurrent nongonococcal urethritis after administration of the treatment regimens currently recommended by the Centers for Disease Control and Prevention.
- #17 However, starting in late 2002, several clinical treatment failures were noted in San Francisco among men who have sex with men and who were treated with azithromycin for early syphilis or as sexual contacts of patients with active syphilis [13]. Molecular analysis of erythromycin-resistant T. pallidum isolates demonstrated a 23S ribosomal RNA mutation that con- ferred resistance to macrolide antibiotics and was associated with treatment failure [14–16]. An extremely high prevalence of the mutation (88%) was found in Dublin, Ireland, andmoderately high prevalences were found in US cities (22% in San Francisco, 13% in Seattle, and 11% in Baltimore). The prevalence of the mutation in other parts of the United States is unknown, because molecular analysis is not routinely available. In San Francisco, a clinical trial comparing azithromycin with BPG for the treatment of sexual contacts of patients with in- fectious syphilis was terminated early by the study’s data safety monitoring board, after 2 treatment failures were reported among 12 patients treated with azithromycin [17]. In this light, caution must be exercised when recommending azithromycin
- #20 Number of diagnoses of gonorrhoea by sex, GUM clinics, England & Wales*: 1925 – 2009 Diagnoses of gonorrhoea rose steadily during the 1960s and 70s and remained at high levels until 1985, thereafter decreasing sharply to their lowest levels since recording began. Diagnoses of gonorrhoea began to rise in the mid-1990s until 2002, since when they have steadily fallen until 2009. The slight increase in diagnoses from 2008 to 2009 may be a real increase or may just reflect the introduction of a new data reporting system in 2009. The decline in the incidence of uncomplicated gonorrhoea between 1985 and 1988 may reflect changes in sexual behaviour brought about in response to the HIV epidemic. The subsequent rise observed from 1994 to 2002 suggested increasing unsafe sexual behaviour during this period.
- #21 Sulphonamide resistance in gonococci results from either oversynthesis of p-aminobenzoic acid, which effectively dilutes the antimicrobial agent, or mutations in the genes encoding dihydropteroate synthetase, which produce a mutant enzyme with reduced affinity for sulphonamide.10 Given that gonococcal dihydrofolate reductase has a low affinity for trimethoprim, which can be further reduced by genetic mutations, the TMP-SMX combination offered little advantage over sulphonamides alone. Early treatment failure due to chromosomal resistance was eventually described and results from serial changes in the structure of penicillin-binding proteins (PBPs) and/or outer membrane permeability. Several genetic loci are involved, including the penA, penB, ponA, mtr and pem genes. Mutation of the penA gene results in four- to eightfold increases in the penicillin MIC as a result of lowered PBP-2 affinity consequent to insertion of asparagine at amino acid position 345.18 19 The likely effect of this insertion is to alter a hydrogen-bonding network involving Asp-346 and the SXN triad motif, composed of Ser-362, Ser-363 and Asn-364, at the active site.19 Further mutations have been described near the C terminus of PBP-2, which lower the rate of acylation for penicillin fivefold relative to wild type through a small disordering of residues in the active site.19 The MtrC-MtrD-MtrE multiple transferable resistance efflux pump expels penicillin, tetracycline and macrolides.20 Mutation of the mtrR locus, which encodes a transcriptional repressor of the mtrCDE operon, increases gonococcal resistance to these agents.21 In the presence of mtr mutations, penB mutations reduce outer membrane permeability and raise the penicillin MIC fourfold, due to adjacent amino acid mutations in porin PorB1b—namely, Gly-120-to-Lys (G120K) or Gly-120-to-Asp (G120D) and Ala-121-to-Asp (A121D).22 23 Combined mutations in the penA, penB and mtr genes can raise the penicillin MIC 120-fold and pem mutations may further modify the expression of these three genes.10 24 Chromosomal resistance may be dependent upon a point mutation in the PBP-1 encoding ponA gene (ponA1), which results in a lower rate of acylation by penicillin.25 In addition, in the laboratory setting, decreased susceptibility to penicillin results from a penC (pilQ2) mutation in strains also containing the mtrR and penB resistance determinants.26 A Glu-666-to-Lys (E666K) mis-sense mutation in the pilQ gene interferes with the formation of the PilQ secretin complex, a major gonococcal outer membrane porin and a key requirement for type IV pilus formation.26 This mutation is not seen in clinical isolates, probably because it compromises type IV pilus function and thus pathogenic potential. The emergence of high-level, plasmid-mediated resistance to penicillin in 1976 marked the effective end of penicillin as a therapeutic agent for gonorrhoea in many areas of the world.27 28 Penicillinase-producing N gonorrhoeae (PPNG) contained plasmids encoding a TEM-1-type β-lactamase. The plasmids were readily transferable between gonococci and PPNG spread rapidly. Several types of penicillinase-producing plasmids have been described, including the Asia, Africa, Toronto, Rio, Nîmes and New Zealand plasmids.29–31 The Asia, Africa and Toronto types have been associated with epidemic outbreaks.29 These β-lactamase plasmids may be characterised as either deletion derivates of the Asia plasmid (Africa, Toronto and Rio) or insertion derivatives of either the Asia (New Zealand) or Africa (Nîmes) plasmids.32 Nearly all isolates collected in the pre-penicillin era had MICs of <0.0125 mg/L (0.02 IU/mL).5, 41 This gradually climbed so that 22% of isolates had MIC ≥0.125 mg/L by 1956,5, 42 and by 1974 11–23% of isolates in some US cities were resistant (MIC ≥0.5 mg/L).43 This MIC rise required numerous escalations in the recommended effective dose of penicillin from 50,000 units in 1945 to 4.8 Million units by the 1970s.5, 44, 45 Increasing low-level penicillin resistance was the additive effect of multiple chromosomal mutations resulting in altered penicillin binding proteins, increased antibiotic efflux, and decreased antimicrobial penetration of the outer membrane.46
- #24 Sulphonamide resistance in gonococci results from either oversynthesis of p-aminobenzoic acid, which effectively dilutes the antimicrobial agent, or mutations in the genes encoding dihydropteroate synthetase, which produce a mutant enzyme with reduced affinity for sulphonamide.10 Given that gonococcal dihydrofolate reductase has a low affinity for trimethoprim, which can be further reduced by genetic mutations, the TMP-SMX combination offered little advantage over sulphonamides alone. Early treatment failure due to chromosomal resistance was eventually described and results from serial changes in the structure of penicillin-binding proteins (PBPs) and/or outer membrane permeability. Several genetic loci are involved, including the penA, penB, ponA, mtr and pem genes. Mutation of the penA gene results in four- to eightfold increases in the penicillin MIC as a result of lowered PBP-2 affinity consequent to insertion of asparagine at amino acid position 345.18 19 The likely effect of this insertion is to alter a hydrogen-bonding network involving Asp-346 and the SXN triad motif, composed of Ser-362, Ser-363 and Asn-364, at the active site.19 Further mutations have been described near the C terminus of PBP-2, which lower the rate of acylation for penicillin fivefold relative to wild type through a small disordering of residues in the active site.19 The MtrC-MtrD-MtrE multiple transferable resistance efflux pump expels penicillin, tetracycline and macrolides.20 Mutation of the mtrR locus, which encodes a transcriptional repressor of the mtrCDE operon, increases gonococcal resistance to these agents.21 In the presence of mtr mutations, penB mutations reduce outer membrane permeability and raise the penicillin MIC fourfold, due to adjacent amino acid mutations in porin PorB1b—namely, Gly-120-to-Lys (G120K) or Gly-120-to-Asp (G120D) and Ala-121-to-Asp (A121D).22 23 Combined mutations in the penA, penB and mtr genes can raise the penicillin MIC 120-fold and pem mutations may further modify the expression of these three genes.10 24 Chromosomal resistance may be dependent upon a point mutation in the PBP-1 encoding ponA gene (ponA1), which results in a lower rate of acylation by penicillin.25 In addition, in the laboratory setting, decreased susceptibility to penicillin results from a penC (pilQ2) mutation in strains also containing the mtrR and penB resistance determinants.26 A Glu-666-to-Lys (E666K) mis-sense mutation in the pilQ gene interferes with the formation of the PilQ secretin complex, a major gonococcal outer membrane porin and a key requirement for type IV pilus formation.26 This mutation is not seen in clinical isolates, probably because it compromises type IV pilus function and thus pathogenic potential. The emergence of high-level, plasmid-mediated resistance to penicillin in 1976 marked the effective end of penicillin as a therapeutic agent for gonorrhoea in many areas of the world.27 28 Penicillinase-producing N gonorrhoeae (PPNG) contained plasmids encoding a TEM-1-type β-lactamase. The plasmids were readily transferable between gonococci and PPNG spread rapidly. Several types of penicillinase-producing plasmids have been described, including the Asia, Africa, Toronto, Rio, Nîmes and New Zealand plasmids.29–31 The Asia, Africa and Toronto types have been associated with epidemic outbreaks.29 These β-lactamase plasmids may be characterised as either deletion derivates of the Asia plasmid (Africa, Toronto and Rio) or insertion derivatives of either the Asia (New Zealand) or Africa (Nîmes) plasmids.32 Plasmid-mediated tetracycline-resistant N gonorrhoeae (TRNG) were first reported in the USA and shortly afterwards in the Netherlands.34 35 The 25.2 MDa (40.6 kb) TRNG plasmid carries the streptococcal tetM determinant responsible for tetracycline resistance.36 The TetM protein reduces the susceptibility of ribosomes to tetracyclines by tetracycline release, competes with elongation factor EF-G and has ribosome-dependent GTPase activity.37 Restriction endonuclease mapping and DNA sequencing demonstrated that the American-type and Dutch-type TRNG plasmids were different.38 39 American-type TRNG were initially described in the UK and Africa, Dutch-type TRNG isolates were reported in Asia and South America, and variants based on restriction endonuclease analysis have also been described in Uruguay and South Africa.40–42 TRNG are now widespread, possibly as a result of widespread use of tetracyclines in STI management.43 Sex Transm Infect 2010;86:415-421 doi:10.1136/sti.2010.042648 Review The Gonococcus fights back: is this time a knock out? David A Lewis1,2,3 + Author Affiliations 1STI Reference Centre, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa 2Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3Division of Medical Microbiology, University of Cape Town, Cape Town, South Africa Correspondence to Professor David A Lewis, STI Reference Centre, National Institute for Communicable Diseases, Private Bag X4, Sandringham 2131, South Africa; [email_address] Contributors In writing this review, the author alone undertook a review of relevant articles in PubMed relating to gonococcal resistance to sulphonamides, penicillin, tetracycline, spectinomycin, aminoglycosides, macrolides, quinolones and cephalosporins on several occasions (last search, April 2010). Historical information was also obtained from older medical text books, books on the history of sexually transmitted infections and relevant review articles, which have been referenced in the current manuscript accordingly. Accepted 7 June 2010 Published Online First 23 July 2010 Next Section Abstract Since the introduction of antibiotics in the 1930s, Neisseria gonorrhoeae has exhibited a remarkable ability to acquire novel genetic resistance determinants. Initially, sulphonamides were replaced by penicillin, while tetracyclines were prescribed for penicillin-allergic patients. With the advent of penicillinase-producing gonococci, spectinomycin was only briefly useful as alternative treatment and plasmid-mediated tetracycline resistance spread rapidly from the mid-1980s onwards. The fluoroquinolones followed but chromosomally mediated resistance appeared after only a decade of use. Seventy years on, we now face a global public health challenge of immense significance—the emergence of resistance to cephalosporins. With lack of investment in the search for new anti-gonococcal antimicrobial agents or vaccine research, the global spread of multiresistant gonococci can be seen. The impact of untreatable gonorrhoea on HIV transmission could be enormous in high-prevalence countries. This threat comes at a time when many national STI control programmes are weak. To delay the emergence of extensively drug-resistant gonorrhoea, public health systems require strengthening and novel strategies need implementing to enhance the therapeutic lifespan of the few antimicrobial agents that we have left. Neisseria gonorrhoeae antibiotic resistance penicillin quinolone cephalosporin ciprofloxacin Previous SectionNext Section Introduction Gonorrhoea is one of the oldest infections known to man and spreads very efficiently through unprotected sexual intercourse. The organism's primary sites of infection involve the mucous membrane of the urethra, endocervix, anal crypts, pharynx and conjunctiva.1 Complications include urethral stricture, urogenital tract abscesses, prostatitis, epididymo-orchitis, pelvic inflammatory disease, blindness and disseminated gonococcal infection.1 Although gonococcal complications are relatively rare today, they were often seen by clinicians in the pre-antibiotic era. Gonorrhoea remains an important sexually transmitted infection (STI) owing to epidemiological synergy with HIV.2 By increasing HIV load in the genital tract, gonorrhoea has the potential to enhance HIV transmission and acquisition.3 With the introduction of improved clinical services and effective antimicrobial agents, gonorrhoea became a manageable disease. The gonococcus has shown itself to be a master of evolutionary adaptation over the past 70 years. Clinical features and patterns of transmission have changed and a number of novel chromosomal and plasmid-mediated antimicrobial resistance mechanisms have been acquired (table 1). The development and spread of multidrug and extensively drug-resistant Neisseria gonorrhoeae once again threatens public health services.4 This review provides a historical perspective on the evolution of antimicrobial resistance by this highly adaptable pathogen. View this table: In this window In a new window Table 1 Summary of the key mechanisms and determinants of gonococcal resistance to antimicrobial agents Previous SectionNext Section The pre-antibiotic era Until the introduction of antibiotics, treatment consisted of rest, abstention from alcohol and sexual activity, systemic treatment with one or other of the balsams and urethral irrigations.5 Acute urethritis was treated by anterior urethral irrigation with a 1/3000 dilution of warm potassium permanganate for 2 weeks. Acute retention of urine was usually relieved by the administration of a soap and water enema, oral laudanum and hot baths; catheterisation was performed in those unresponsive to conservative management. Many clinicians performed urethroscopy on male patients after resolution of symptoms to detect persistent glandular infections and to dilate the urethra in cases of anterior and posterior urethral strictures. During the first world war, soldiers received prophylactic packets containing condoms, calomel ointment and Argyrol. Post-coital treatment centres, comprising a urethral irrigation facility, were also set up in many barracks. Previous SectionNext Section Sulphonamides The discovery of sulphanilamide by Gerhard Domagk in 1935 was a major breakthrough.5 Subsequent studies in Germany, UK and the USA showed that sulphanilamide could cure 80–90% of gonorrhoea cases.6 However, by 1944, many gonococci were clinically resistant and, by the end of the decade, over 90% of N gonorrhoeae isolates were microbiologically resistant to sulphonamides.6 7 Subsequent combination treatment with trimethoprim and sulfamethoxazole (TMP-SMX) was used with success in the 1970s, although with the disadvantage that patients required multidose treatment.8 9 Sulphonamide resistance in gonococci results from either oversynthesis of p-aminobenzoic acid, which effectively dilutes the antimicrobial agent, or mutations in the genes encoding dihydropteroate synthetase, which produce a mutant enzyme with reduced affinity for sulphonamide.10 Given that gonococcal dihydrofolate reductase has a low affinity for trimethoprim, which can be further reduced by genetic mutations, the TMP-SMX combination offered little advantage over sulphonamides alone. Previous SectionNext Section Penicillins Cecil Paine, a microbiologist working in Sheffield, was the first person to use a crude extract from Penicillium notatum to cure gonococcal infection in an infant with ophthalmia in 1930.11 Penicillin was first used to treat gonococcal urethritis in 1943. Although initially reserved for sulphonamide-resistant cases, penicillin subsequently became the drug of choice for gonorrhoea.12–14 Initially, cure rates with penicillin exceeded 95% and total doses as low as 45 mg were prescribed owing to scarcity and the high cost of the drug.13 Over time, gonococci became less susceptible as penicillin minimum inhibitory concentrations (MICs) rose, requiring higher doses to effect cure.15–17 Early treatment failure due to chromosomal resistance was eventually described and results from serial changes in the structure of penicillin-binding proteins (PBPs) and/or outer membrane permeability. Several genetic loci are involved, including the penA, penB, ponA, mtr and pem genes. Mutation of the penA gene results in four- to eightfold increases in the penicillin MIC as a result of lowered PBP-2 affinity consequent to insertion of asparagine at amino acid position 345.18 19 The likely effect of this insertion is to alter a hydrogen-bonding network involving Asp-346 and the SXN triad motif, composed of Ser-362, Ser-363 and Asn-364, at the active site.19 Further mutations have been described near the C terminus of PBP-2, which lower the rate of acylation for penicillin fivefold relative to wild type through a small disordering of residues in the active site.19 The MtrC-MtrD-MtrE multiple transferable resistance efflux pump expels penicillin, tetracycline and macrolides.20 Mutation of the mtrR locus, which encodes a transcriptional repressor of the mtrCDE operon, increases gonococcal resistance to these agents.21 In the presence of mtr mutations, penB mutations reduce outer membrane permeability and raise the penicillin MIC fourfold, due to adjacent amino acid mutations in porin PorB1b—namely, Gly-120-to-Lys (G120K) or Gly-120-to-Asp (G120D) and Ala-121-to-Asp (A121D).22 23 Combined mutations in the penA, penB and mtr genes can raise the penicillin MIC 120-fold and pem mutations may further modify the expression of these three genes.10 24 Chromosomal resistance may be dependent upon a point mutation in the PBP-1 encoding ponA gene (ponA1), which results in a lower rate of acylation by penicillin.25 In addition, in the laboratory setting, decreased susceptibility to penicillin results from a penC (pilQ2) mutation in strains also containing the mtrR and penB resistance determinants.26 A Glu-666-to-Lys (E666K) mis-sense mutation in the pilQ gene interferes with the formation of the PilQ secretin complex, a major gonococcal outer membrane porin and a key requirement for type IV pilus formation.26 This mutation is not seen in clinical isolates, probably because it compromises type IV pilus function and thus pathogenic potential. The emergence of high-level, plasmid-mediated resistance to penicillin in 1976 marked the effective end of penicillin as a therapeutic agent for gonorrhoea in many areas of the world.27 28 Penicillinase-producing N gonorrhoeae (PPNG) contained plasmids encoding a TEM-1-type β-lactamase. The plasmids were readily transferable between gonococci and PPNG spread rapidly. Several types of penicillinase-producing plasmids have been described, including the Asia, Africa, Toronto, Rio, Nîmes and New Zealand plasmids.29–31 The Asia, Africa and Toronto types have been associated with epidemic outbreaks.29 These β-lactamase plasmids may be characterised as either deletion derivates of the Asia plasmid (Africa, Toronto and Rio) or insertion derivatives of either the Asia (New Zealand) or Africa (Nîmes) plasmids.32 Previous SectionNext Section Tetracyclines Tetracyclines were discovered in the late 1940s and were used initially to treat gonorrhoea in patients allergic to penicillin. Tetracyclines were effective in post-gonococcal urethritis and are today often given as additional treatment for suspected or proven chlamydial co-infection. Gonococci became less susceptible to tetracycline over time and chromosomal resistance soon appeared.16 The main mechanism of tetracycline resistance in gonococci involves ribosomal protection, whereby binding of tetracyclines to the bacterial ribosome is impaired. It is due to a Val-57-to-Met (V57M) point mutation in the rpsJ (tet-2) gene encoding ribosomal protein S10.33 Additional combined mutations in the penB, penC and mtr loci, modified by mutations in the tem gene, may further decrease N gonorrhoeae susceptibility by increasing efflux and bacterial cell entry of tetracyclines.24 26 Plasmid-mediated tetracycline-resistant N gonorrhoeae (TRNG) were first reported in the USA and shortly afterwards in the Netherlands.34 35 The 25.2 MDa (40.6 kb) TRNG plasmid carries the streptococcal tetM determinant responsible for tetracycline resistance.36 The TetM protein reduces the susceptibility of ribosomes to tetracyclines by tetracycline release, competes with elongation factor EF-G and has ribosome-dependent GTPase activity.37 Restriction endonuclease mapping and DNA sequencing demonstrated that the American-type and Dutch-type TRNG plasmids were different.38 39 American-type TRNG were initially described in the UK and Africa, Dutch-type TRNG isolates were reported in Asia and South America, and variants based on restriction endonuclease analysis have also been described in Uruguay and South Africa.40–42 TRNG are now widespread, possibly as a result of widespread use of tetracyclines in STI management.43 Previous SectionNext Section Spectinomycin and aminoglycosides Spectinomycin was developed and marketed specifically for the treatment of gonorrhoea in the early 1960s. It was useful for treating gonorrhoea caused by PPNG although is not effective in treating pharyngeal gonorrhoea.44 45 Spectinomycin resistance was first reported in a penicillin susceptible gonococcus in the Netherlands in 1967, and subsequently in a PPNG isolate acquired in the Philippines in 1981.46 47 Spectinomycin was introduced as first-line treatment for US military personnel in the former Republic of Korea in 1981 but, after only 4 years, an 8.2% treatment failure rate was reported, which resulted in the replacement of spectinomycin with ceftriaxone.48 49 Kanamycin is cheap and sometimes used to treat gonorrhoea in Indonesia.50 51 Gentamicin is the national first-line treatment for gonorrhoea in Malawi and has also been used to treat gonococcal infections in Mongolia.51–53 Data on clinical resistance are few and the microbiological resistance breakpoints uncertain. Studies in Malawi confirm that gonococci remain susceptible after 14 years of first-line use.54 Although it is known that aminoglycosides bind to the bacterial ribosome and inhibit protein synthesis, their precise mode of action remains unclear.55 Several mechanisms of aminoglycoside resistance have been described among bacteria, including decreased drug uptake and accumulation, modification of the ribosomal target, drug efflux and enzymatic drug modification.55 Among gonococci, it appears that resistance is drug-specific and due to single-step mutations in various loci rather than enzymatic inactivation.10 56 The loci responsible for spectinomycin (spc) and streptomycin (str) resistance are genetically linked. The kanamycin resistance locus (kan) is located between the spc and str loci and also linked to the spc, str and rif loci. These loci are thought to represent a cluster of genes encoding for ribosomal proteins.10
- #25 Macrolides act by binding to the 50S ribosomal subunit and inhibit the elongation of peptide chains. Bacterial resistance to these antimicrobial agents may result from drug efflux and/or modification of the ribosomal target, by either methylase-associated modification of 23S rRNA or genetic mutations in 23S rRNA.62 The MtrR repressor-regulated MtrC-MtrD-MtrE efflux system of N gonorrhoeae exports macrolides. Increased efflux may occur by deletion or insertional inactivation of either the mtrR gene or the mtrR promoter.20 63 64 Another macrolide efflux pump, encoded by mef, has been detected in some isolates, although its contribution to gonococcal macrolide resistance remains unclear.65 Expression of several 23S RNA methylases, encoded by the ermB, ermC and ermF genes, is responsible for modification of the gonococcal ribosomal target.66 67 These methylase genes are associated with conjugative transposons which facilitate interbacterial spread.66 Mutations in the peptidyltransferase loop of domain V of 23S rRNA also confer gonococcal resistance to macrolides.68
- #26 Quinolones interfere with bacterial DNA metabolism by the inhibition of two enzymes, DNA gyrase and topoisomerase IV. In Gram-negative bacteria, DNA gyrase is the primary target, whereas topoisomerase IV appears to be more important in Gram-positive bacteria. DNA gyrase, which catalyses supercoiling of linear DNA, is composed of GyrA and GyrB subunits, encoded by gyrA and gyrB, respectively. The function of topoisomerase IV, encoded by parC, is poorly understood. Characteristic point mutations within quinolone resistance determining regions of gyrA and parC genes are associated with resistance. Resistance is normally seen in gonococci with gyrA mutations alone or with mutations in both gyrA and parC genes
- #27 Historical perspective on antimicrobial resistance in the United States.QRNG = quinolone-resistant Neisseria gonorrhoeae; MSM = men who have sex with men.
- #28 Since therapeutic failure has not been seen, the relationship between in vitro testing and the dosage given to patients is unknown as such the cut-off for decreased cefixime susceptibility is currently tentative. There is the accepted cut-off at MIC≥0.25mg/l but we have also considered a slightly lower cut-off of MIC≥0.125mg/l. Decreased susceptibility to cefixime MIC≥0.25mg/l was 1.2% in 2009. At the lower cut-off (MIC≥0.125mg/l) decreased susceptibility first emerged in 2005 (0.1%). It has since increased from 2.8% in 2008 to 10.6% in 2009
- #29 Cefixime MICs varied by gender and sexual orientation. Most of the isolates were found among MSM particularly isolates at the lower cut off (MIC≥0.125mg/l).
- #30 Isolates demonstrating decreased susceptibility to cefixime (MIC≥0.25mg/l) came from all three gender and sexual orientation groups. In 2009, 0.9% of heterosexual men, 2.5% of MSM and 0.3% of women had isolates with decreased susceptibility to cefixime.
- #31 Decreased susceptibility to ceftriaxone (MIC ≥0.125mg/l) was first observed in a single isolate in 2005 (0.1%). In 2009, 4 (0.3%) isolates seen through GRASP demonstrated decreased susceptibility to this antimicrobial.
- #32 Ceftriaxone MICs vary by gender and sexual orientation. MSM were more often likely to have isolates with much higher MICs than heterosexual men and women.
- #33 The prevalence of decreased susceptible ceftriaxone (MIC ≥0.125mg/l) isolates among MSM in 2009 was 0.8% compared to 1.2% in 2008. There were no isolates with decreased susceptibility to ceftriaxone among heterosexual men or women in 2009.
- #34 Ciprofloxacin resistance continues to be high among MSM between 2008 and 2009, resistance increased significantly from 45.9% to 54.0%. Ciprofloxacin resistance among heterosexual men and women was considerably lower. In 2009, 28.7% of heterosexual men and 15.1% of women had ciprofloxacin resistant gonococcal isolates.
- #35 Ciprofloxacin resistance has always been higher among Asians and individuals of white ethnicities. The higher proportion of cases among these ethnic groups are thought to be a result of sexual contact in countries of origin among Asians and higher proportions of MSM among individuals of white ethnicity. Ciprofloxacin resistance is much lower in black ethnic groups particularly black Caribbeans.
- #36 Since 2001, there have been fairly low resistance to azithromycin and spectinomycin among GRASP isolates. In 2007, high level resistance, that is isolates with (MIC≥256mg/l) were observed for the first time. These six isolates came from an even split of heterosexual men and women.
- #43 Gentamicin MIC distributions in 17 countries participating in Euro-GASP, 2009.
- #47 Matsumoto, T.InstitutionDepartment of Urology, School of Medicine, University of Occupational and Environmental Health, Japan. t-matsu@med.uoeh-u.ac.jpTitleTrends of sexually transmitted diseases and antimicrobial resistance in Neisseria gonorrhoeae.SourceInternational Journal of Antimicrobial Agents. 31 Suppl 1:S35-9, 2008 Feb.
- #48 Furuya R. Tanaka M.Authors Full NameFuruya, Ryusaburo. Tanaka, Masatoshi.InstitutionDepartment of Urology, Faculty of Medicine, Fukuoka University.Title[Neisseria gonorrhoeae infections]. [Review] [10 refs] [Japanese]SourceNippon Rinsho - Japanese Journal of Clinical Medicine. 67(1):129-35, 2009 Jan.AbstractNeisseria gonorrhoeae infections are common bacterial sexually transmitted diseases. Men will usually experience lower urinary tract symptons attributed to urethritis, epididymitis, proctitis, or prostatitis, with associated mucopurulent urethral discharge. Many women are asymptomatic. But, occasionally, they have symptons of vaginal and pelvic discomfort of dysuria, and these infections can lead to pelvic inflammatory disease. Recentry, high prevalence of Neisseria gonorrhoeae isolates resistant to antimicrobial agents is a serious problem in the treatment of gonorrhea. For example, in Fukuoka city, Japan, the proportion of the isolates resistant to ciprofloxacin (CPFX) were 73.4% in 2006 and it was still so high. The proportion of the isolates resistant to tetracycline (TC) was 38.5% in 2006 and that of isolates resistant to penicillin G (PCG) was 17.5%. Owing to this high prevalence of antimicrobial-resistant Neisseria gonorrhoeae in Japan, the clinical efficacy rates of oral antimicrobial agents have become lower. So, as first-line therapy for gonococcal infections, only three parenteral regimens of single doses of ceftriaxone, cefodizime or spectinomycin are recommended by the Japanese Society for Sexually Transmitted Diseases. In the circumstances, we studied in vitro activity of combinations of oral agents such as, beta-lactam and azithromycin, fluoroquinolone and azithromycin, or beta-lactam and fluoroquinolone against Neisseria gonorrhoeae. The cefixime+azithromycin combination demonstrated greater synergy than other combinations. Int J STD AIDS. 2007 Apr;18(4):253-4. The treatment of pharyngeal gonorrhoea with a single oral dose of cefixime. McMillan A, Young H. Department of Genitourinary Medicine, NHS Lothian University Hospitals Division, Edinburgh, UK. a.amcmm@btopenworld.com Comment in: Int J STD AIDS. 2007 Sep;18(9):647-8. An audit of the efficacy treatment of pharyngeal gonorrhoea with a single oral dose of 400 mg of cefixime was undertaken; 83% of patients also received a single oral dose of azithromycin to treat possible concurrent anogenital chlamydial infection. Of the 54 patients studied, only one of 45 patients who attended for at least one test of cure had a positive culture seven days after treatment; the possibility of reinfection could not have been excluded. Two tests of cure were obtained from 18 patients. Cefixime, therefore, seems to be effective in the treatment of pharyngeal gonorrhoea.
- #50 Two cases of failed ceftriaxone treatment in pharyngeal gonorrhoea verified by molecular microbiological methods John Tapsall1, Phillip Read2, Christopher Carmody3, Christopher Bourne2, Sanghamitra Ray1, Athena Limnios1, Theo Sloots4 and David Whiley4 J Med Microbiol 58 (2009), 683-687 Diagnostic, genotypic and antibiotic-resistance determinants of Neisseria gonorrhoeae were analysed by molecular methods to verify the failure of ceftriaxone treatment in two cases of pharyngeal gonorrhoea. Monoplex assays were needed to define competitive inhibition of a positive Chlamydia PCR in a duplex assay. Different penA changes were detected in the N. gonorrhoeae isolated from the two cases. These were associated with raised ceftriaxone MICs of 0.03 and 0.016 mg l–1, which may have contributed to the treatment failures in these cases. Chisholm SA. Neal TJ. Alawattegama AB. Birley HD. Howe RA. Ison CA.Emergence of high-level azithromycin resistance in Neisseria gonorrhoeae in England and Wales.Journal of Antimicrobial Chemotherapy. 64(2):353-8, 2009 Aug.AbstractOBJECTIVES: This study aimed to investigate the origin of high-level azithromycin resistance that emerged in isolates of Neisseria gonorrhoeae in England and Wales in 2007, and to establish methods for identifying high-level azithromycin resistance. METHODS: The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) data from 2001-07 were examined for emerging trends in azithromycin susceptibility. Further to the identification of six high-level azithromycin-resistant isolates in GRASP 2007, an additional 102 isolates were selected on the basis of azithromycin susceptibility and geographic origin from the GRASP 2006 and 2007 collections. Susceptibility testing by Etest and disc diffusion was performed on all 108 isolates and 75 of these were typed by N. gonorrhoeae multiantigen sequence typing. RESULTS: A slight drift towards higher MICs of azithromycin was observed in the gonococcal population since 2001. Of greater concern was the first example of a shift to high-level resistance observed in six isolates in 2007. All six isolates were sequence type 649, which was not observed in any of the lower-level azithromycin-resistant isolates from 2007 or in any isolates tested from the same geographical locations. Contact tracing data for one patient suggested a link with Scotland. Disc diffusion testing of all 108 isolates showed that azithromycin, but not erythromycin, discs can differentiate between low-level and high-level resistance. CONCLUSIONS: High-level azithromycin resistance has emerged in England and Wales. Contact tracing and typing data suggest this may have originated from Scotland. Surveillance of azithromycin resistance will be key in controlling its further dissemination Curr Opin Infect Dis. 2009 Feb;22(1):87-91. Neisseria gonorrhoeae and emerging resistance to extended spectrum cephalosporins. Tapsall JW. World Health Collaborating Centre for STDs, Department of Microbiology, The Prince of Wales Hospital, Sydney, Australia. j.tapsall@unsw.edu.au PURPOSE OF REVIEW: Antibiotic resistance in Neisseria gonorrhoeae poses on-going problems for individual case management and disease control for gonorrhoea. Considerable reliance is now placed on third-generation cephalosporins for the treatment of gonorrhoea following the loss of efficacy of penicillins and quinolones. Current clinical and laboratory perspectives on N. gonorrhoeae with decreased susceptibility to third-generation cephalosporins are provided. RECENT FINDINGS: Treatment failures following therapy with the oral third-generation cephalosporins cefixime and ceftibuten have been reported, but not with the injectable ceftriaxone. The gonococci involved have raised minimal inhibitory concentrations to these agents, including to ceftriaxone. The presence of multiple chromosomal changes form the basis for this 'resistance', prominent among which is a mosaic penicillin-binding protein 2 found in association with additional known and unknown mutations in other genes. The imprecise nature of laboratory criteria for detecting these gonococci means that the distribution and prevalence of these strains is also uncertain. SUMMARY: Concerns regarding the appearance of gonococci associated with treatment failure with oral cephalosporins are increasing. The origins, causes and patterns of spread of these clinically resistant gonococci are reminiscent of the earlier experiences with quinolone-resistant gonococci. Preventive measures require simultaneous implementation of disease-control principles, coupled with those for antimicrobial resistance
- #52 http://chem3513-2007.pbworks.com/w/page/15648409/Antibiotic-Resistance Certain types of bacteria are able to undergo natural transformation, which means that they are capable of obtaining small pieces of free DNA from the environment and incorporating it into either their genome or the cell. The DNA obtained is not necessarily a plasmid but if another bacterium containing a resistance plasmid has lysed and that plasmid is not left in the environment it is possible for another bacteria to uptake that plasmid and incorporate it, hence that bacterium which was not previously resistant to a particular antibiotic is now resistant. The next method of horizontal gene transfer is known as conjugation. Conjugation occurs when there is direct cell to cell contact between any two bacteria and a small piece of DNA, usually a plasmid, is transferred from one bacterium to the other. In conjugation the bacteria need not be related, or even the same strain, the only requirement is that both bacteria need to be able to undergo conjugation. The final method of horizontal gene transfer is that of Transduction. Transduction occurs when viruses specific to bacteria, known as bacteriophage, obtain host DNA and transport this DNA to the next bacteria it infects. Usually this only occurs between bacteria which are related (Yim, 2007). Once the plasmid has been incorporated into the bacterial cell, the plasmid codes for resistance a certain antibiotic according to the mechanisms previously described above. Of the mechanisms listed, as seen in figure 6, there are 3 common mechanisms usually used; antibiotic degrading enzymes, antibiotic altering enzymes, and efflux pumps (Yim, 2007).
- #58 Background: It is widely thought that widespread antibiotic use selects for community antibiotic resistance, though this has been difficult to prove in the setting of a community-randomized clinical trial. In this study, we used a randomized clinical trial design to assess whether macrolide resistance was higher in communities treated with mass azithromycin for trachoma, compared to untreated control communities. Methods and Findings: In a cluster-randomized trial for trachoma control in Ethiopia, 12 communities were randomized to receive mass azithromycin treatment of children aged 1–10 years at months 0, 3, 6, and 9. Twelve control communities were randomized to receive no antibiotic treatments until the conclusion of the study. Nasopharyngeal swabs were collected from randomly selected children in the treated group at baseline and month 12, and in the control group at month 12. Antibiotic susceptibility testing was performed on Streptococcus pneumoniae isolated from the swabs using Etest strips. In the treated group, the mean prevalence of azithromycin resistance among all monitored children increased from 3.6% (95% confidence interval [CI] 0.8%–8.9%) at baseline, to 46.9% (37.5%–57.5%) at month 12 (p = 0.003). In control communities, azithromycin resistance was 9.2% (95% CI 6.7%–13.3%) at month 12, significantly lower than the treated group (p,0.0001). Penicillin resistance was identified in 0.8% (95% CI 0%–4.2%) of isolates in the control group at 1 year, and in no isolates in the children-treated group at baseline or 1 year. Conclusions: This cluster-randomized clinical trial demonstrated that compared to untreated control communities, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to intensive azithromycin treatment. Mass azithromycin distributions were given more frequently than currently recommended by the World Health Organization’s trachoma program. Azithromycin use in this setting did not select for resistance to penicillins, which remain the drug of choice for pneumococcal infections. S. pneumoniae was isolated from 76 of 110 nasopharyngeal samples collected from the treated arm before mass azithromycin treatments (mean prevalence of S. pneumoniae carriage 69.1% [95% CI 56.7%–81.7%]), and from 93 of 119 samples 12 mo after the baseline treatment (78.0% [68.0%–86.7%]) (Table 2). Data was collected from the control group at month 12 only; in this untreated group, S. pneumoniae was isolated in 98 of 120 nasopharyngeal samples (81.7% [95% CI 75.8%–89.2%])
- #73 Historical perspective on antimicrobial resistance in the United States.QRNG = quinolone-resistant Neisseria gonorrhoeae; MSM = men who have sex with men.
- #81 From 2002/3, cefixime has been one of the recommended treatments for gonorrhoea. Although resistance has never been noted to cefixime (or any other third generation cephalosporins) in England or Wales, from 2006, isolates have begun to show decreased susceptibility to this treatment. Overall, 20 GUM patients have shown decreased susceptibility to cephalosporins (two in 2007 and 18 in 2008). Please note: this resistance data is weighted to take in to account differences in retrieval rates of isolates.
- #82 Although fluctuations in the rates of resistance for MSM were noted in the last few years, it does appear that, in MSM overall, CMRNG resistance is increasing. In 2000, CMRNG resistance in MSM stood at 4.6%. This rose to a high of 30.8% in 2007 before settling at 18.0% in 2008. This is compared to an overall resistance for all sexual orientations of 8.5% in 2008. Please note: this resistance data is weighted to take in to account differences in retrieval rates of isolates.
- #83 In 2002/3, the recommended treatment for gonorrhoea changed from fluoroquinolones (ciprofloxacin) to third-generation cephalosporins (cefixime and ceftriaxone). Although the rates of prescription of fluoroquinolones has decreased dramatically, ciprofloxacin resistance seems to be stabilising at 28%. This may indicate that a decrease in selective pressure on Neisseria gonorrhoeae may not result in a simultaneous decrease in antimicrobial resistance for that particular antimicrobial. Similarly, as proportions of patients receiving cephalosporins has increased, we have noted decreased susceptibility to cephalopsorins beginning to emerge. Please note: this resistance data is weighted to take in to account differences in retrieval rates of isolates.
- #84 Ciprofloxacin resistance is especially high in those of self-reported Asian and white ethnicity. As ciprofloxacin resistance in the Far East is extremely high (approaching 100% in some regions), high rates of ciprofloxacin resistance in those of Asian ethnicity in England and Wales may indicate that some of this resistance is being imported by those that have sex while travelling abroad. Please note: this resistance data is weighted to take in to account differences in retrieval rates of isolates.