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1.  Adverse drug events resulting from use of drugs with sulphonamide-containing anti-malarials and artemisinin-based ingredients: findings on incidence and household costs from three districts with routine demographic surveillance systems in rural Tanzania 
Malaria Journal  2013;12:236.
Anti-malarial regimens containing sulphonamide or artemisinin ingredients are widely used in malaria-endemic countries. However, evidence of the incidence of adverse drug reactions (ADR) to these drugs is limited, especially in Africa, and there is a complete absence of information on the economic burden such ADR place on patients. This study aimed to document ADR incidence and associated household costs in three high malaria transmission districts in rural Tanzania covered by demographic surveillance systems.
Active and passive surveillance methods were used to identify ADR from sulphadoxine-pyrimethamine (SP) and artemisinin (AS) use. ADR were identified by trained clinicians at health facilities (passive surveillance) and through cross-sectional household surveys (active surveillance). Potential cases were followed up at home, where a complete history and physical examination was undertaken, and household cost data collected. Patients were classified as having ‘possible’ or ‘probable’ ADR by a physician.
A total of 95 suspected ADR were identified during a two-year period, of which 79 were traced, and 67 reported use of SP and/or AS prior to ADR onset. Thirty-four cases were classified as ‘probable’ and 33 as ‘possible’ ADRs. Most (53) cases were associated with SP monotherapy, 13 with the AS/SP combination (available in one of the two areas only), and one with AS monotherapy. Annual ADR incidence per 100,000 exposures was estimated based on ‘probable’ ADR only at 5.6 for AS/SP in combination, and 25.0 and 11.6 for SP monotherapy. Median ADR treatment costs per episode ranged from US$2.23 for those making a single provider visit to US$146.93 for patients with four visits. Seventy-three per cent of patients used out-of-pocket funds or sold part of their farm harvests to pay for treatment, and 19% borrowed money.
Both passive and active surveillance methods proved feasible methods for anti-malarial ADR surveillance, with active surveillance being an important complement to facility-based surveillance, given the widespread practice of self-medication. Household costs associated with ADR treatment were high and potentially catastrophic. Efforts should be made to both improve pharmacovigilance across Africa and to identify strategies to reduce the economic burden endured by households suffering from ADR.
PMCID: PMC3710484  PMID: 23844934
Anti-malarial; Adverse drug reactions; Household costs; ACT; Sulphonamide; Tanzania
2.  Urinary tract infections treated with single dose of short-acting sulphonamide. 
British Medical Journal  1979;1(6172):1175-1176.
In a prospective study 29 patients with urinary tract infections caused by sulphonamide-sensitive organisms were treated with a single oral dose of the short-acting sulphonamide sulphafurazole. Twenty-seven (93%) of the 29 patients--and possibly all 29--were cured of their infections. There was no difference in the recurrence rates after single-dose treatment and treatment for 10 days or more. Six out of eight strains of Escherichia coli causing early recurrences were sensitive to sulphonamides. These results suggest that uncomplicated infections may safely and successfully be treated by a single oral dose of a short-acting sulphonamide.
PMCID: PMC1599338  PMID: 444997
3.  The novel toluidine sulphonamide EL102 shows pre-clinical in vitro and in vivo activity against prostate cancer and circumvents MDR1 resistance 
British Journal of Cancer  2013;109(8):2131-2141.
Taxanes are routinely used for the treatment of prostate cancer, however the majority of patients eventually develop resistance. We investigated the potential efficacy of EL102, a novel toluidine sulphonamide, in pre-clinical models of prostate cancer.
The effect of EL102 and/or docetaxel on PC-3, DU145, 22Rv1 and CWR22 prostate cancer cells was assessed using cell viability, cell cycle analysis and PARP cleavage assays. Tubulin polymerisation and immunofluorescence assays were used to assess tubulin dynamics. CWR22 xenograft murine model was used to assess effects on tumour proliferation. Multidrug-resistant lung cancer DLKPA was used to assess EL102 in a MDR1-mediated drug resistance background.
EL102 has in vitro activity against prostate cancer, characterised by accumulation in G2/M, induction of apoptosis, inhibition of Hif1α, and inhibition of tubulin polymerisation and decreased microtubule stability. In vivo, a combination of EL102 and docetaxel exhibits superior tumour inhibition. The DLKP cell line and multidrug-resistant DLKPA variant (which exhibits 205 to 691-fold greater resistance to docetaxel, paclitaxel, vincristine and doxorubicin) are equally sensitive to EL102.
EL102 shows potential as both a single agent and within combination regimens for the treatment of prostate cancer, particularly in the chemoresistance setting.
PMCID: PMC3798953  PMID: 24052043
prostate cancer; chemotherapeutic; toluidine sulphonamide; taxane; MDR1 drug resistance; Hif1
4.  Abundances of Tetracycline, Sulphonamide and Beta-Lactam Antibiotic Resistance Genes in Conventional Wastewater Treatment Plants (WWTPs) with Different Waste Load 
PLoS ONE  2014;9(8):e103705.
Antibiotics and antibiotic resistant bacteria enter wastewater treatment plants (WWTPs), an environment where resistance genes can potentially spread and exchange between microbes. Several antibiotic resistance genes (ARGs) were quantified using qPCR in three WWTPs of decreasing capacity located in Helsinki, Tallinn, and Tartu, respectively: sulphonamide resistance genes (sul1 and sul2), tetracycline resistance genes (tetM and tetC), and resistance genes for extended spectrum beta-lactams (blaoxa-58, blashv-34, and blactx-m-32). To avoid inconsistencies among qPCR assays we normalised the ARG abundances with 16S rRNA gene abundances while assessing if the respective genes increased or decreased during treatment. ARGs were detected in most samples; sul1, sul2, and tetM were detected in all samples. Statistically significant differences (adjusted p<0.01) between the inflow and effluent were detected in only four cases. Effluent values for blaoxa-58 and tetC decreased in the two larger plants while tetM decreased in the medium-sized plant. Only blashv-34 increased in the effluent from the medium-sized plant. In all other cases the purification process caused no significant change in the relative abundance of resistance genes, while the raw abundances fell by several orders of magnitude. Standard water quality variables (biological oxygen demand, total phosphorus and nitrogen, etc.) were weakly related or unrelated to the relative abundance of resistance genes. Based on our results we conclude that there is neither considerable enrichment nor purification of antibiotic resistance genes in studied conventional WWTPs.
PMCID: PMC4118896  PMID: 25084517
5.  A novel phenoxy thiophene sulphonamide molecule protects against glutamate evoked oxidative injury in a neuronal cell model 
BMC Neuroscience  2013;14:93.
Glutamate is one of the major neurotransmitters in the central nervous system. It is a potent neurotoxin capable of neuronal destruction through numerous signal pathways when present in high concentration. Glutamate-evoked excitotoxicity has been implicated in the etiology of many neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and ischemic stroke. Increasing evidence has shown that reactive oxygen species (ROS) provoked by glutamate-linked oxidative stress plays a crucial role in the pathogenesis of these disorders. We previously reported the discovery of an aryl thiophene compound, 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B355252) from a proprietary library of small molecules. We showed that this compound was capable of potentiating nerve growth factor (NGF)-primed neurite outgrowth in neuronal cell models in a low NGF environment. In the present study we investigated the neuroprotective effects and signaling pathways of B355252 on glutamate-evoked excitotoxicity in HT-22, a murine hippocampal neuronal cell line.
Glutamate significantly decreased HT-22 neuronal cell viability in a concentration-dependent manner as measured by the MTT assay. Co-treatment with 2, 4, and 8 μM B355252 protected against cell death caused by glutamate-induced toxicity by 9.1% (p<0.01), 26.0% (p<0.001), and 61.9% (p<0.001) respectively, compared to glutamate-treated control group. B355252 at a concentration of 8 μM fully rescued HT-22 from the neurototoxic effects of glutamate, and by itself increased cell viability by 16% (p<0.001) above untreated control. Glutamate enhanced reduction in glutathione (GSH) synthesis was reversed by 15% (p<0.01) in the presence of B355252. B355252 reduced the expression of apoptosis inducing factor (AIF) by 27%, while the proapoptotic Bcl-2 associated X protein (Bax) was strongly attenuated 3-fold. Glutamate-evoked increase in intracellular calcium (Ca2+) load and subsequent ROS production was inhibited by 71% (p<0.001) and 40% (p<0.001) respectively, to comparable level as untreated control in the presence of B355252. Glutamate significantly upregulated the phosphorylation of extracellular signal regulated kinase Erk1/2 (pERK1/2), while decreasing Erk3. In contrast, B355252 potently attenuated the glutamate-dependent activation of Erk1/2 and robustly increased the level of ERK3 in HT-22.
A novel phenoxy thiophene small molecule, B355252, suppresses glutamate-evoked oxidative stress in HT-22 neurons by blocking Ca2+ and ROS production, and altering the expression or phosphorylation states of Erk kinases. This molecule previously reported to enhance neurite outgrowth in the presence of sub-physiological concentrations of NGF appears to be a promising drug candidate for development as a potential therapeutic and neuroprotective agent for various neurodegenerative disorders.
PMCID: PMC3846642  PMID: 24004478
Glutamate; Neuroprotection; Excitotoxicity; Small molecule; Alzheimer’s disease; Oxidative stress; ERK3; Neurodegenerative disease; Phenoxy thiophene; HT-22
6.  Sulphonamide resistant commensal Neisseria with alterations in the dihydropteroate synthase can be isolated from carriers not exposed to sulphonamides 
BMC Microbiology  2002;2:34.
Development of sulphonamide resistance in Neisseria meningitidis has been suggested to involve horizontal DNA-transfer from a commensal Neisseria species. In this study, we isolated commensal Neisseria from throat specimens and examined the isolates with respect to sulphonamide resistance.
Three resistant clones were identified and the resistance phenotype could be explained by amino acid variations in their dihydropteroate synthase, the target molecule for sulphonamides. Some of these variations occurred in positions corresponding to previously detected variations in resistant N. meningitidis.
Sulphonamide resistant commensal Neisseria were isolated from an environment not exposed to sulphonamides, suggesting that resistant Neisseria has become a natural part of the commensal throat flora.
PMCID: PMC138796  PMID: 12435277
7.  Antimicrobial susceptibility/resistance and genetic characteristics of Neisseria gonorrhoeae isolates from Poland, 2010-2012 
In Poland, gonorrhoea has been a mandatorily reported infection since 1948, however, the reported incidences are likely underestimated. No antimicrobial resistance (AMR) data for Neisseria gonorrhoeae has been internationally reported in nearly four decades, and data concerning genetic characteristics of N. gonorrhoeae are totally lacking. The aims of this study were to investigate the AMR to previously and currently recommended gonorrhoea treatment options, the main genetic resistance determinant (penA) for extended-spectrum cephalosporins (ESCs), and genotypic distribution of N. gonorrhoeae isolates in Poland in 2010-2012.
N. gonorrhoeae isolates cultured in 2010 (n = 28), 2011 (n = 92) and 2012 (n = 108) in Warsaw and Bialystok, Poland, were examined using antimicrobial susceptibility testing (Etest), pyrosequencing of penA and N. gonorrhoeae multi-antigen sequence typing (NG-MAST).
The proportions of N. gonorrhoeae isolates showing resistance were as follows: ciprofloxacin 61%, tetracycline 43%, penicillin G 22%, and azithromycin 8.8%. No isolates resistant to ceftriaxone, cefixime or spectinomycin were found. However, the proportion of isolates with an ESC MIC = 0.125 mg/L, i.e. at the resistance breakpoint, increased significantly from none in 2010 to 9.3% and 19% in 2012 for ceftriaxone and cefixime, respectively. Furthermore, 3.1% of the isolates showed multidrug resistance, i.e., resistance to ciprofloxacin, penicillin G, azithromycin, and decreased susceptibility to cefixime (MIC = 0.125 mg/L). Seventy-six isolates (33%) possessed a penA mosaic allele and 14 isolates (6.1%) contained an A501V/T alteration in penicillin-binding protein 2. NG-MAST ST1407 (n = 58, 25% of isolates) was the most prevalent ST, which significantly increased from 2010 (n = 0) to 2012 (n = 46; 43%).
In Poland, the diversified gonococcal population displayed a high resistance to most antimicrobials internationally previously recommended for gonorrhoea treatment and decreasing susceptibility to the currently recommended ESCs. The decreasing susceptibility to ESCs was mostly due to the introduction of the internationally spread multidrug-resistant NG-MAST ST1407 in 2011. It is essential to promptly revise the gonorrhoea treatment guidelines, improve the gonorrhoea laboratory diagnostics, and implement quality assured surveillance of gonococcal AMR (ideally also treatment failures) in Poland.
PMCID: PMC3922028  PMID: 24502606
Neisseria gonorrhoeae; Gonorrhoea; Poland; Antimicrobial resistance (AMR); Extended-spectrum cephalosporins (ESCs); Ceftriaxone; Cefixime; penA; NG-MAST
8.  Incidence and antimicrobial susceptibility of Neisseria gonorrhoeae isolates from patients attending the national Neisseria gonorrhoeae reference laboratory of Hungary 
BMC Infectious Diseases  2014;14:433.
The Hungarian national guidelines for the treatment of gonorrhoea were published in 2002 but are now widely considered to be outdated. Improved knowledge is needed with respect to the epidemiology and antimicrobial susceptibility of Neisseria gonorrhoeae strains currently circulating in Hungary not least for the construction of updated local recommendations for treating gonorrhoea. European guidelines are based mostly on western European data raising concerns locally that recommended treatments might not be optimised for the situation in Hungary. We report our recent study on the distribution of antibiotic resistance in various Hungarian (East European) Neisseria gonorrhoeae strains isolated from patients with gonorrhoea over the past four years.
Between January 2010 and December 2013, isolates of N. gonorrhoeae were obtained from sexually active individuals during medical examination at the STD Center of Semmelweis University in Budapest. The minimal inhibitory concentrations (MIC) of azithromycin, cefixime, ceftriaxone, ciprofloxacin, penicillin, tetracycline and spectinomycin were determined to establish the antimicrobial susceptibility of the strains currently circulating in patients that attend our clinic.
Among the 9097 patients tested, 582 had an N. gonorrhoeae infection as detected by culture. The isolates were all sensitive to ceftriaxone and spectinomycin and 581/582 strains were sensitive to cefixime. In contrast, the number of detected strains with elevated azithromycin MIC did increase over the time period examined to approximately 16% in 2013. There was a high percentage of detected resistance to penicillin (77%), tetracycline (86%), and ciprofloxacin (66%) in the isolates examined in this study.
Current European guidelines recommend 2 g azithromycin in addition to 500 mg ceftriaxone as first choice therapy for gonorrhoea. For the purposes of revising the Hungarian national treatment guidelines, apparent increasing resistance to azithromycin during the last four years should be accounted for. It is also clear that penicillin, tetracycline and ciprofloxacin are inappropriate treatment measures at least locally. We also recommend that culture should form part of the diagnostic pathway of gonorrhoea, followed by antibiotic susceptibility testing with MIC determination. This will provide valuable continued monitoring of antibiotic resistance development in strains of Neisseria gonorrhoeae circulating in Hungary.
PMCID: PMC4155111  PMID: 25098185
Neisseria gonorrhoeae; Antimicrobial resistance; Incidence; MIC; Hungary
9.  Antimicrobial susceptibility/resistance and NG-MAST characterisation of Neisseria gonorrhoeae in Belarus, Eastern Europe, 2010–2013 
Gonorrhoea and widely spread antimicrobial resistance (AMR) in its etiological agent Neisseria gonorrhoeae are major public health concerns worldwide. Gonococcal AMR surveillance nationally and internationally, to identify emerging resistance and inform treatment guidelines, is imperative for public health purposes. In 2009, AMR surveillance was initiated in Belarus, Eastern Europe because no gonococcal AMR data had been available for at least two decades. Herein, the prevalence and trends of gonococcal AMR and molecular epidemiological characteristics of N. gonorrhoeae strains from 2010 to 2013 in Belarus, are described.
N. gonorrhoeae isolates (n=193) obtained in the Mogilev (n=142), Minsk (n=36) and Vitebsk (n=15) regions of Belarus in 2010 (n=72), 2011 (n=6), 2012 (n=75) and 2013 (n=40) were analyzed in regards to AMR using the Etest method and for molecular epidemiology with N. gonorrhoeae multi-antigen sequence typing (NG-MAST).
During 2010–2013, the proportions of resistant N. gonorrhoeae isolates were as follows: tetracycline 36%, ciprofloxacin 28%, penicillin G 9%, azithromycin 5%, and cefixime 0.5%. Only one (0.5%) β-lactamase producing isolate was detected. No isolates resistant to ceftriaxone and spectinomycin were identified. Overall, the resistance levels to tetracycline, ciprofloxacin and penicillin G were relatively stable. Interestingly, the level of resistance to azithromycin declined from 12% in 2010 to 0% in 2013 (P < 0.05). In total, 70 NG-MAST STs were identified. The predominant STs were ST1993 (n=53), ST807 (n=13), ST285 (n=8) and ST9735 (n=8). Many novel STs (n=43, 61%), representing 41% of all isolates, were found.
During 2010–2013, the N. gonorrhoeae population in Belarus displayed high and relatively stable resistance levels to tetracycline, ciprofloxacin, and penicillin G, while the resistance to azithromycin declined. One isolate was resistant to cefixime, but no resistance to ceftriaxone or spectinomycin was found. The results of the present surveillance initiated in 2009 were also used to replace penicillin G with ceftriaxone (1 g single dose intramuscularly) as the first-line drug for empiric treatment of gonorrhoea in the national treatment guidelines in Belarus in late 2009. It is essential to further strengthen the surveillance of gonococcal AMR and ideally survey also treatment failures and molecular epidemiological genotypes in Belarus.
PMCID: PMC4316755  PMID: 25637258
Neisseria gonorrhoeae; Gonorrhoea; Antimicrobial resistance; Surveillance; Extended-spectrum cephalosporins (ESCs); Ceftriaxone; Cefixime; Treatment; N. gonorrhoeae multiantigen sequence typing (NG-MAST); Belarus
10.  Antimicrobial susceptibility and genetic characteristics of Neisseria gonorrhoeae isolates from Vietnam, 2011 
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major public health concern worldwide. In Vietnam, knowledge regarding N. gonorrhoeae prevalence and AMR is limited, and data concerning genetic characteristics of N. gonorrhoeae is totally lacking. Herein, we investigated the phenotypic AMR (previous, current and possible future treatment options), genetic resistance determinants for extended-spectrum cephalosporins (ESCs), and genotypic distribution of N. gonorrhoeae isolated in 2011 in Hanoi, Vietnam.
N. gonorrhoeae isolates from Hanoi, Vietnam isolated in 2011 (n = 108) were examined using antibiograms (Etest for 10 antimicrobials), Neisseria gonorrhoeae multi-antigen sequence typing (NG-MAST), and sequencing of ESC resistance determinants (penA, mtrR and penB).
The levels of in vitro resistance were as follows: ciprofloxacin 98%, tetracycline 82%, penicillin G 48%, azithromycin 11%, ceftriaxone 5%, cefixime 1%, and spectinomycin 0%. The MICs of gentamicin (0.023-6 mg/L), ertapenem (0.002-0.125 mg/L) and solithromycin (<0.016-0.25 mg/L) were relatively low. No penA mosaic alleles were found, however, 78% of the isolates contained an alteration of amino acid A501 (A501V (44%) and A501T (34%)) in the encoded penicillin-binding protein 2. A single nucleotide (A) deletion in the inverted repeat of the promoter region of the mtrR gene and amino acid alterations in MtrR was observed in 91% and 94% of the isolates, respectively. penB resistance determinants were detected in 87% of the isolates. Seventy-five different NG-MAST STs were identified, of which 59 STs have not been previously described.
In Vietnam, the highly diversified gonococcal population displayed high in vitro resistance to antimicrobials previously recommended for gonorrhoea treatment (with exception of spectinomycin), but resistance also to the currently recommended ESCs were found. Nevertheless, the MICs of three potential future treatment options were low. It is essential to strengthen the diagnostics, case reporting, and epidemiologic surveillance of gonorrhoea in Vietnam. Furthermore, the surveillance of gonococcal AMR and gonorrhoea treatment failures is imperative to reinforce. Research regarding novel antimicrobial treatment strategies (e.g., combination therapy) and new antimicrobials is crucial for future treatment of gonorrhoea.
PMCID: PMC3574855  PMID: 23351067
Neisseria gonorrhoeae; Gonorrhoea; Vietnam; Antimicrobial resistance; Extended-spectrum cephalosporins (ESCs); Ceftriaxone; Cefixime; Resistance determinants; penA; NG-MAST
11.  Gonorrhoea 
BMJ Clinical Evidence  2007;2007:1604.
In the UK, diagnoses rates for gonorrhoea in 2005 were 196/100,000 for 20-24 year old men, and 133/100,000 for 16-19 year old women. Co-infection with Chlamydia trachomatis is reported in 10-40% of people with gonorrhoea in the USA and UK.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for uncomplicated infections in men and non-pregnant women; and in pregnant women? What are the effects of treatments for disseminated gonococcal infection? What are the effects of dual treatment for gonorrhoea and chlamydia infection? We searched: Medline, Embase, The Cochrane Library and other important databases up to July 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotic regimens (dual treatment, multiple dose, single dose).
Key Points
Gonorrhoea is caused by infection with Neisseria gonorrhoeae. In men, uncomplicated urethritis is the most common manifestation while in women only about half of cases produce symptoms (such as vaginal discharge and dyspareunia). In the UK, diagnoses rates for gonorrhoea were 196/100 000 for 20-24 year old men and 133/100 000 for 16-19 year old women in 2005.Co-infection with Chlamydia trachomatis is reported in 10-40% of people with gonorrhoea in the USA and UK.
Single dose antibiotic regimens have achieved cure rates of 95% or higher in men and non-pregnant women with urogenital or rectal gonorrhoea. However, resistance to many widely available antibiotics (e.g. penicillins, tetracylines, fluoroquinolones) continues to spread, making it necessary to consider local N gonorrhoeae susceptibility patterns when choosing a treatment regimen. Single dose antibiotics are also effective for curing gonorrhoea in pregnant women.
In people with disseminated gonococcal infection, there is consensus that multidose regimens using injectable cephalosporins or fluoroquinolones (when the infecting organism is known to be susceptible) are the most effective treatments, although evidence supporting this is somewhat sparse.
We did not find any sufficient evidence to judge the best treatment for people with both gonorrhoea and chlamydia, although theory, expert opinion, and clinical experience suggest a combination of antimicrobials active against both N gonorrhoeae and C trachomatis are effective.
PMCID: PMC2943790  PMID: 19454057
12.  Gonorrhoea 
BMJ Clinical Evidence  2011;2011:1604.
In the UK, diagnosis rates for gonorrhoea in 2008 were 152/100,000 for men aged 20 to 24 years and 135/100,000 for women aged 16 to 19 years. Resistance to one or more antimicrobial agent is reported in more than one quarter of isolates. Co-infection with Chlamydia trachomatis is reported in 10% to 40% of people with gonorrhoea in the US and UK.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for uncomplicated infections in men and non-pregnant women; and in pregnant women? What are the effects of treatments for disseminated gonococcal infection? What are the effects of dual treatment for gonorrhoea and chlamydia infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotic regimens (dual treatment, multiple dose, single dose).
Key Points
Gonorrhoea is caused by infection with Neisseria gonorrhoeae. In men, uncomplicated urethritis is the most common manifestation, while in women less than half of cases produce symptoms (such as vaginal discharge and dyspareunia). Rates of diagnosed gonorrhoea infection in the UK fell by more than 30% between 2002 and 2009.In the UK in 2008, diagnosis rates for gonorrhoea were 152/100,000 for men aged 20 to 24 years, and 135/100,000 for women aged 16 to 19 years.Rates are highest in men aged 20 to 24 years and women aged 16 to 19 years.In the UK, some studies have shown that 28% of isolates are resistant to ciprofloxacin and 8% to penicillin. There is evidence of reduced susceptibility to cephalosporins.Co-infection with Chlamydia trachomatis is reported in 10% to 40% of people with gonorrhoea in the US and UK.
Single-dose antibiotic regimens have achieved cure rates of 95% and higher in men and non-pregnant women with urogenital or rectal gonorrhoea, although we don't know how different single-dose antibiotic regimens compare with each other. Single-dose antibiotics are also effective for curing gonorrhoea in pregnant women.
In people with disseminated gonococcal infection, there is consensus that multiple-dose regimens using cephalosporins or fluoroquinolones (when the infecting organism is known to be susceptible) are the most effective treatments, although evidence supporting this is somewhat sparse.
We found insufficient evidence to judge the best treatment for people with both gonorrhoea and chlamydia, although theory, expert opinion, and clinical experience suggest that a combination of antimicrobials active against both N gonorrhoeae and C trachomatis is effective.
PMCID: PMC3275146  PMID: 21401969
13.  Enhancing Gonococcal Antimicrobial Resistance Surveillance: a Real-Time PCR Assay for Detection of Penicillinase-Producing Neisseria gonorrhoeae by Use of Noncultured Clinical Samples▿ 
Journal of Clinical Microbiology  2011;49(2):513-518.
With increasing concerns regarding diminishing treatment options for gonorrhea, maintaining the efficacy of currently used treatments and ensuring optimal Neisseria gonorrhoeae antimicrobial resistance surveillance are of the utmost importance. Penicillin is still used to treat gonorrhea in some parts of the world. In this study, we developed and validated a real-time PCR assay for the detection of penicillinase-producing N. gonorrhoeae (PPNG) in noncultured clinical samples with the aim of enhancing penicillin resistance surveillance. The assay (PPNG-PCR2) was designed to be an indirect marker of penicillinase activity, by targeting a region of sequence predicted to be conserved across all N. gonorrhoeae plasmid types harboring the beta-lactamase gene while not specifically targeting the actual beta-lactamase-encoding sequence. The assay was evaluated by using a total of 118 N. gonorrhoeae clinical isolates and 1,194 clinical specimens, including 239 N. gonorrhoeae-positive clinical samples from which N. gonorrhoeae cells were isolated and for which phenotypic penicillinase results are available. Overall, the PPNG-PCR2 assay provided 100% sensitivity and 98.7% specificity compared to bacterial culture results for the detection of PPNG in clinical specimens. PPNG-PCR2 false-positive results, presumably due to cross-reactions with unrelated bacterial species, were observed for up to 1.3% of clinical samples but could be distinguished on the basis of high cycle threshold values. In tandem with phenotypic surveillance, the PPNG-PCR2 assay has the potential to provide enhanced epidemiological surveillance of N. gonorrhoeae penicillin resistance and is of particular relevance to regions where penicillin is still used to treat gonorrhea.
PMCID: PMC3043482  PMID: 21159935
14.  Neisseria gonorrhoeae non-susceptible to cephalosporins and quinolones in Northwest Ethiopia 
BMC Infectious Diseases  2013;13:415.
The occurrence of antibiotic resistant Neisseria gonorrhoeae isolates is a serious public health problem in different corners of the globe. The objective of this study was to analyze the antimicrobial susceptibility pattern of N. gonorrhoeae in Northwest Ethiopia.
This was a retrospective study of N. gonorrhoeae isolated from genital swabs of patients referred to the Amhara Regional Health Research Laboratory between September 2006 and June 2012 in Bahir Dar, Ethiopia. A structured check list was used to collect socio-demographic and laboratory variables. Data were analyzed using SPSS software version 16.
Out of 352 genital specimens processed, 29 clinical strains of N. gonorrhoeae were identified. The percentage of N. gonorrhoeae isolates non-susceptible to ceftriaxone, ciprofloxacin, tetracycline and penicillin G was 27.8%, 40.9%, 92.6% and 94.4% respectively. Twenty percent of the isolates were found to be non-susceptible to both ceftriaxone and ciprofloxacin. Non-susceptibility to an injectable cephalosporin and any two of quinolones, penicillins or tetracyclines was observed in 27.8% of the isolates. The percentage of N. gonorrhoeae which were non-susceptible to tetracycline or penicillin G was high throughout the study period. However, the percentage of fluoroquinolone or cephalosporine non-susceptible strains showed an increasing trend.
A high percentage of N. gonorrhoeae isolated from genital specimens in Northwest Ethiopia are non-susceptible to an injectable cephalosporin and any two of quinolones, penicillins or tetracyclines. Treatment of gonorrhea in the study area needs to be guided by antibiotic susceptibility testing of isolates.
PMCID: PMC3844457  PMID: 24007340
Non-susceptible; Neisseria gonorrhoeae; Ethiopia
15.  Long-term Control of Bacteriuria with Trimethoprim-Sulphonamide 
British Medical Journal  1971;1(5745):377-379.
Long-term antibacterial therapy with the drug combination trimethoprim-sulphonamide has been used for the treatment of 52 patients with persistent or recurrent bacteriuria. Hypersensitivity or gastrointestinal intolerance was observed in six. Bacteriuria was controlled in 36 out of 38 patients with organisms sensitive to trimethoprim-sulphonamide, 28 having received treatment for periods ranging from 6 to 49 months. Treatment was in some cases curative and in others suppressive or prophylactic. The importance of supportive measures is re-emphasized.
PMCID: PMC1795024  PMID: 5541926
16.  Resistant Urinary Infections Resulting from Changes in Resistance Pattern of Faecal Flora Induced by Sulphonamide and Hospital Environment* 
British Medical Journal  1970;3(5718):305-309.
The faecal flora was studied in eight children admitted to hospital for treatment of a first urinary infection with sulphonamides. The original, sulphonamide-sensitive Escherichia coli organisms were found to disappear, to be replaced by other E. coli serotypes that were almost invariably resistant to sulphonamides. Some of these serotypes carried R-factors for multiple antibiotic resistance.
Possibly some urinary infections with antibiotic-resistant organisms may be due to faecal organisms whose resistance has been changed by previous antibiotic treatment. Hence it is important to study the effects of individual antibiotics on the faecal flora.
PMCID: PMC1701508  PMID: 4916195
17.  Sensitivity of Nocardia to trimethoprim and sulphonamides in vitro 
Journal of Clinical Pathology  1970;23(5):423-426.
Studies in vitro of the sensitivity to trimethoprim and sulphonamides of nine strains of N. asteroides, two strains of N. caviae, and one of N. blackwellii are presented. No unequivocal evidence of synergism was found. Despite this, the inclusion of trimethoprim in the drug regime when sulphonamides are used in the treatment of nocardiosis is suggested on empirical grounds.
PMCID: PMC476784  PMID: 5476868
18.  A haematological study of patients receiving long-term treatment with trimethoprim and sulphonamide 
Journal of Clinical Pathology  1970;23(5):392-396.
The haematological effects of long-term treatment for three months with a combination of trimethoprim and sulphamethoxazole were studied in 10 cases of chronic bronchitis. Trimethoprim selectively inhibits dihydrofolate reductase in bacteria but not in man. Only minor effects on folate metabolism were observed in nine cases, causing no clinical concern. Some degree of thrombocytopenia occurred in the tenth case which improved when folinic acid was given.
PMCID: PMC476778  PMID: 4920413
19.  The calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide directly blocks human ether à-go-go-related gene potassium channels stably expressed in human embryonic kidney 293 cells 
British Journal of Pharmacology  2010;161(4):872-884.
N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide (W-7) is a well-known calmodulin inhibitor used to study calmodulin regulation of intracellular Ca2+ signalling-related process. Here, we have determined whether W-7 would inhibit human ether gene (hERG or Kv11.1) potassium channels, hKv1.5 channels or hKIR2.1 channels expressed in human embryonic kidney (HEK) 293 cells.
The hERG channel current, hKv1.5 channel current or hKIR2.1 channel current was recorded with a whole-cell patch clamp technique.
It was found that the calmodulin inhibitor W-7 blocked hERG, hKv1.5 and hKIR2.1 channels. W-7 decreased the hERG current (IhERG) in a concentration-dependent manner (IC50: 3.5 µM), and the inhibition was more significant at depolarization potentials between +10 and +60 mV. The hERG mutations in the S6 region Y652A and F656V, and in the pore helix S631A, had the IC50s of 5.5, 9.8 and 25.4 µM respectively. In addition, the compound inhibited hKv1.5 and hKIR2.1 channels with IC50s of 6.5 and 13.4 µM respectively.
These results indicate that the calmodulin inhibitor W-7 exerts a direct channel-blocking effect on hERG, hKv1.5 and hKIR2.1 channels stably expressed in HEK 293 cells. Caution should be taken in the interpretation of calmodulin regulation of ion channels with W-7.
PMCID: PMC2992901  PMID: 20860665
W-7; hERG channel; hKv1.5; hKIR2.1
20.  Synthesis, Characterization, and Biotoxicity of N N⌢ Donor Sulphonamide Imine Silicon(IV) Complexes 
The organosilicon derivatives of 2-[1-(2-furayl)ethyledene]sulphathiazole with organosilicon chlorides have been synthesised and characterized on the basis of analytical, conductance, and spectroscopic techniques. Probable trigonal bipyramidal and octahedral structures for the resulting derivatives have been proposed on the basis of electronic, IR, 1H, 13C NMR, and 29Si NMR spectral studies. In the search for better fungicides, bactericides, nematicides, and insecticides studies were conducted to assess the growth-inhibiting potential of the synthesized complexes against various pathogenic fungal, bacterial strains, root-knot nematode Meloidogyne incognita, and insect Trogoderma granarium. These studies demonstrate that the concentrations reached levels which are sufficient to inhibit and kill the pathogens, nematode, and insect.
PMCID: PMC1686292  PMID: 17496998
21.  Synergism between sulphonamide drugs and antibiotics of the polymyxin group against Proteus sp. in vitro 
Journal of Clinical Pathology  1963;16(4):362-366.
Interesting synergism in vitro between a recently introduced antibiotic, colistin methane sulphonate, and sulphonamide drugs is described. The observations were extended to polymyxin B sulphate and sulphonamides with essentially similar results. The combinations are bactericidal at therapeutic levels, the ratio of drugs to one another is not critical, and the effect is present over a fairly wide pH range.
PMCID: PMC480577  PMID: 14044038
22.  Ortho-toluene sulphonamide and saccharin in the promotion of bladder cancer in the rat. 
British Journal of Cancer  1980;42(1):129-147.
The importance of the contaminant OTS in the promoting activity of commercial saccharin on rat bladder neoplasia was investigated. OTS, OTS-free and OTS-contaminated saccharin were administered in the drinking water or diet for 2 years to groups of rats pretreated with an intravesical instillation of MNU; OTS alone and OTS-free saccharin were also given to groups of rats not pretreated with MNU. Administration of OTS was not associated with changes in urinary pH, crystalluria or calculus formation, had no effect on the histology of normal rat bladder, and did not increase the incidence of bladder hyperplasia or neoplasia elicited by pretreatment with MNU. No differences could be found between the effect of OTS-free or OTS-contaminated saccharin on bladders of rats pretreated with MNU. These results indicate that OTS contamination played no part in the reported promoting activity of saccharin on the rat bladder. Administration of saccharin did not increase urinary pH, crystalluria or calculus formation, and failed to promote bladder neoplasia after a carcinogenic dose of MNU, though the numbers of proliferative lesions in the bladder were increased.
PMCID: PMC2010463  PMID: 7426324
23.  GW627368X ((N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl} benzene sulphonamide): a novel, potent and selective prostanoid EP4 receptor antagonist 
British Journal of Pharmacology  2006;148(3):326-339.
N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl}benzene sulphonamide (GW627368X) is a novel, potent and selective competitive antagonist of prostanoid EP4 receptors with additional human TP receptor affinity.At recombinant human prostanoid EP4 receptors expressed in HEK293 cells, GW627368X produced parallel rightward shifts of PGE2 concentration–effect (E/[A]) curves resulting in an affinity (pKb) estimate of 7.9±0.4 and a Schild slpoe not significantly different from unity. The affinity was independent of the agonist used.In rings of phenylephrine precontracted piglet saphenous vein, GW627368X (30–300 nM) produced parallel rightward displacement of PGE2 E/[A] curves (pKb=9.2±0.2; slope=1).GW627368X appears to bind to human prostanoid TP receptors but not the TP receptors of other species. In human washed platelets, GW627368X (10 μM) produced 100% inhibition of U-46619 (EC100)-induced aggregation (approximate pA2 ∼7.0). However, in rings of rabbit and piglet saphenous vein and of guinea-pig aorta GW627368X (10 μM) did not displace U-46619 E/[A] curves indicating an affinity of <5.0 for rabbit and guinea-pig prostanoid TP receptors.In functional assays GW627368X is devoid of both agonism and antagonist affinity for prostanoid CRTH2, EP2, EP3, IP and FP receptors. At prostanoid EP1 receptors, GW627368X was an antagonist with a pA2 of 6.0, and at prostanoid IP receptors the compound increased the maximum effect of iloprost by 55%. At rabbit prostanoid EP2 receptors the pA2 of GW627368X was <5.0.In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP4 and TP receptors (pKi=7.0±0.2 (n=10) and 6.8 (n=2), respectively). Affinity for all other human prostanoid receptors was <5.3.GW627368X will be a valuable tool to explore the role of the prostanoid EP4 receptor in many physiological and pathological settings.
PMCID: PMC1751567  PMID: 16604093
GW627368X; EP4; prostanoid; receptor; competitive; antagonist
24.  The incidence of gonorrhoea and the antibiotic sensitivity of gonococci in Australia, 1981-1991. The Australian Gonococcal Surveillance Programme. 
Genitourinary Medicine  1993;69(5):364-369.
OBJECTIVE--To review and analyse the changing incidence of gonorrhoea and the increasing antibiotic resistance in gonococci in Australia from 1981 to 1991. DESIGN--Use of data from the sample of gonorrhoea in Australia examined by the Australian Gonococcal Surveillance Programme (AGSP), a continuing long-term multi-centric study of gonococcal disease and gonococcal susceptibility to antibiotics, over the period 1 July, 1981 to 30 June, 1991. RESULTS--Over 32,000 cases and strains from defined sources were examined in the 10 year study period. The number of cases of gonorrhoea in the sample decline from a peak of 6599 in 1982-1983 to 1121 in the final year under review, a reduction of 83%. Periods when greater than average reductions in incidence occurred in different groups were noted. Ano-rectal gonorrhoea in men decreased sharply in 1985 during an overall decline of 92.5% recorded between 1 July, 1981 to 30 June, 1987. However, the incidence of ano-rectal cases in males rose in subsequent years while gonorrhoea, overall, continued to decrease and at a greater rate after 1985. Antibiotic resistance in gonococci in Australia was manifested both as a progressive increase in the levels of intrinsic resistance to the penicillins and through the appearance and spread of penicillinase-producing N gonorrhoeae (PPNG). At the end of the review period in June, 1991, 8.8% of gonococcal isolates in Australia showed high levels of intrinsic resistance to the penicillins and 13% of strains were PPNG. These separate mechanisms of resistance appeared at different times in different parts of Australia, and their importance also varied throughout the country. Most infections with PPNG were acquired by men overseas whereas most women with PPNG were infected locally. Endemic spread of PPNG was a significant problem in Sydney and Melbourne, but decreased in importance in the later years of the study. CONCLUSIONS--In the past decade a large reduction in the incidence of gonorrhoea and, by implication, other STDs has occurred in the past decade in Australia. In some groups of patients the decline in incidence is continuing while in others a slight increase has been noted. Resistance to antibiotics of gonococci in Australia was mainly restricted to the penicillins, but through both chromosomal and plasmid-mediated mechanisms. This resistance was seen particularly in Sydney and Melbourne where endemic cycles of transmission of PPNG were established, and in infected travellers from S-E Asia in other centres. Valid and comparable, and regionally relevant data are a continuing requirement for assessing and modifying antibiotic treatment regimens for gonococcal disease.
PMCID: PMC1195119  PMID: 8244354
25.  Antimicrobial susceptibility of Neisseria gonorrhoeae isolates from symptomatic men attending the Nanjing sexually transmitted diseases clinic (2011–2012): genetic characteristics of isolates with reduced sensitivity to ceftriaxone 
BMC Infectious Diseases  2014;14:622.
Evolving gonococcal antimicrobial resistance (AMR) poses a serious threat to public health. The aim of this study was to: update antimicrobial susceptibility data of Neisseria gonorrhoeae recently isolated in Nanjing, China and identify specific deteminants of antimicrobial resistance and gentoypes of isolates with decreased sensitivity to ceftriaxone.
334 N. gonorrhoeae isolates were collected consecutively from symptomatic men attending the Nanjing STD Clinic between April 2011 and December 2012. The minimum inhibitory concentrations (MICs) for penicillin, tetracycline, ciprofloxacin, spectinomycin and ceftriaxone were determined by agar plate dilution for each isolate. Penicillinase-producing N. gonorrhoeae (PPNG) and tetracycline-resistant N. gonorrhoeae (TRNG) were examined and typed for β-lactamase and tetM encoding plasmids respectively. Isolates that displayed elevated MICs to ceftriaxone (MIC ≥0.125 mg/L) were also tested for mutations in penA, mtrR, porB1b, ponA and pilQ genes and characterized by Neisseria gonorrhoeae multi-antigen sequence typing (NG-MAST).
98.8% (330/334) of N. gonorrhoeae isolates were resistant to ciprofloxacin; 97.9% (327/334) to tetracycline and 67.7% (226/334) to penicillin. All isolates were susceptible to ceftriaxone (MIC ≤0.25 mg/L) and spectinomycin (MIC ≤32 mg/L). Plasmid mediated resistance was exhibited by 175/334 (52%) of isolates: 120/334 (36%) of isolates were PPNG and 104/334 (31%) were TRNG. 90.0% (108/120) of PPNG isolates carried the Asia type β-lactamase encoding plasmid and 96% (100/104) of TRNG isolates carried the Dutch type tetM containing plasmid. Elevated MICs for ceftriaxone were present in 15 (4.5%) isolates; multiple mutations were found in penA, mtrR, porB1b and ponA genes. The 15 isolates were distributed into diverse NG-MAST sequence types; four different non-mosaic penA alleles were identified, including one new type.
N. gonorrhoeae isolates in Nanjing generally retained similar antimicrobial resistance patterns to isolates obtained five years ago. Fluctuations in resistance plasmid profiles imply that genetic exchange among gonococcal strains is ongoing and is frequent. Ceftriaxone and spectinomycin remain treatments of choice of gonorrhea in Nanjing, however, decreased susceptibility to ceftriaxone and rising MICs for spectinomycin of N. gonorrhoeae isolates underscore the importance of maintaining surveillance for AMR (both phenotypic and genotypic).
PMCID: PMC4263019  PMID: 25427572
Neisseria gonorrhoeae; Antimicrobial resistance; Resistance plasmids; Ceftriaxone; Resistance determinants

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