Associations between antimicrobial susceptibility/resistance of Neisseria gonorrhoeae isolates in European Union/European Economic Area and patients' gender, sexual orientation and anatomical site of infection, 2009-2016.

BACKGROUND: The emergence and spread of antimicrobial resistance (AMR) in Neisseria gonorrhoeae, nationally and internationally, is a serious threat to the management and control of gonorrhoea. Limited and conflicting data regarding the epidemiological drivers of gonococcal AMR internationally have been published. We examined the antimicrobial susceptibility/resistance of gonococcal isolates (n = 15,803) collected across 27 European Union/European Economic Area (EU/EEA) countries in 2009-2016, in conjunction to epidemiological and clinical data of the corresponding patients, to elucidate associations between antimicrobial susceptibility/resistance and patients' gender, sexual orientation and anatomical site of infection. METHODS: In total, 15,803 N. gonorrhoeae isolates from the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP), 2009-2016, were examined. Associations between gonococcal susceptibility/resistance and patients' gender, sexual orientation and anatomical site of infection were investigated using univariate and multivariate logistic regression analysis. Statistical significance was determined by Pearson χ2-test or Fisher's exact test with two-tailed p-values of < 0.05 indicating significance. RESULTS: The overall gonococcal resistance from 2009 to 2016 was 51.7% (range during the years: 46.5-63.5%), 7.1% (4.5-13.2%), 4.3% (1.8-8.7%), and 0.2% (0.0-0.5%) to ciprofloxacin, azithromycin, cefixime, and ceftriaxone, respectively. The level of resistance combined with decreased susceptibility to ceftriaxone was 10.2% (5.7-15.5%). Resistance to cefixime and ciprofloxacin, and resistance combined with decreased susceptibility to ceftriaxone were positively associated with urogenital infections and heterosexual males, males with sexual orientation not reported and females (except for ciprofloxacin), i.e. when compared to men-who-have-sex-with-men (MSM). Azithromycin resistance was positively associated with heterosexual males, but no association was significant regarding anatomical site of infection. CONCLUSIONS: Overall, sexual orientation was the main variable associated with gonococcal AMR. Strongest positive associations were identified with heterosexual patients, particularly males, and not MSM. To provide evidence-based understanding and mitigate gonococcal AMR emergence and spread, associations between antimicrobial susceptibility/resistance and patients' gender, sexual orientation and anatomical site of infection need to be further investigated in different geographic settings. In general, these insights will support identification of groups at increased risk and targeted public health actions such as intensified screening, 3-site testing using molecular diagnostics, sexual contact tracing, and surveillance of treatment failures.

External quality assessment (EQA) of Neisseria gonorrhoeae antimicrobial susceptibility testing in primary laboratories in Germany.

BACKGROUND: Worldwide, an increase in antimicrobial resistance (AMR) of Neisseria gonorrhoeae has been observed. Until now, no protocol for an external quality assessment (EQA) has been available for Germany. The German gonococcal resistance network (GORENET) performed an EQA of primary laboratories in Germany in order to assess quality of antibiotic susceptibility testing, to gain information about laboratory procedures and to assess the impact of these procedures on test results. METHODS: Laboratories assessed drug susceptibility to cefixime, ceftriaxone, azithromycin, penicillin and ciprofloxacin for five N. gonorrhoeae strains, using their standard laboratory protocols. Minimal inhibitory concentrations (MICs) were compared to World Health Organisation (WHO) consensus results (or, if not available, reference laboratory results), while deviation by +/- one doubling dilution was accepted. Data on laboratory procedures were collected via a standardised questionnaire. Generalized linear models and conditional inference trees (CTREE) were used to assess relationships between laboratory procedures and testing outcomes. RESULTS: Twenty-one primary laboratories participated in the EQA in June 2018. 96% of ciprofloxacin MICs were reported within accepted deviations, as well as 88% for cefixime, 85% for ceftriaxone, 79% for penicillin and 70% for azithromycin. The use of interpretation standards and general laboratory procedures like agar base, incubation settings or the use of control strains strongly differed between laboratories. In statistical analysis, incubation time of cultures < 24 h was associated with correct measurements. Additionally, a 5% CO2 concentration was associated with correct results regarding azithromycin compared to 3%. CTREE analysis showed that incubation time, humidity and CO2 concentration had the greatest influence on the average deviation from consensus results. CONCLUSIONS: In conclusion, we report the development of a protocol for N. gonorrhoeae antimicrobial susceptibility testing in Germany. While testing results were in accordance with the expected consensus results in 70-96%, depending on the antibiotic agent, laboratory methodology was heterogeneous and may significantly affect the testing quality. We therefore recommend the development of a standard operating procedure (SOP) for N. gonorrhoeae susceptibility testing in Germany.

The European gonococcal antimicrobial surveillance programme (Euro-GASP) appropriately reflects the antimicrobial resistance situation for Neisseria gonorrhoeae in the European Union/European Economic Area.

BACKGROUND: European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) antimicrobial resistance (AMR) data are used to inform gonorrhoea treatment guidelines; therefore the data need to be robust and representative. We assessed the extent to which Euro-GASP reflects national measures of the AMR situation for Neisseria gonorrhoeae across the European Union/European Economic Area (EU/EEA). METHODS: We compared data from Euro-GASP with published national gonococcal AMR data from 15 countries for azithromycin, cefixime and ciprofloxacin for the period 2009 to 2013 and performed Poisson regression to identify differences (p < 0.05) between the proportions of resistant isolates. The 2014 Euro-GASP AMR data for each country (n = 19) were weighted to account for differences in the distribution of patient characteristics between Euro-GASP and EU/EEA epidemiological gonorrhoea surveillance data. Data were compared to determine whether estimates of resistance levels differed with regards to the 5% threshold used to assess the clinical utility of first-line gonorrhoea treatments. We assessed the quality of decentralised testing by comparing AMR data for isolates tested both centrally and in the participating laboratories, and by evaluating external quality assessment (EQA) performance. RESULTS: There was no significant difference for azithromycin, cefixime and ciprofloxacin resistance when Euro-GASP country data were compared with data from national reports. Weighting slightly altered the Euro-GASP AMR estimates (by between - 4.7 and 4.7% from the unweighted estimates). Weighting resulted in greater changes in estimates of resistance to azithromycin (from - 9.5 to 2.7%) and ciprofloxacin (from - 14.8 to 17.9%) in countries with low isolate numbers and low completeness of reporting (n = 3). Weighting caused AMR levels to fall below or above the 5% threshold for cefixime or azithromycin, respectively in only two countries. Susceptibility category data submitted from the decentralised Euro-GASP laboratories were concordant with the Euro-GASP data (> 90%). EQA performance was also good; < 5% of the minimum inhibitory concentration (MIC) results differed by > 4-fold from the modal MIC of the EQA isolate. CONCLUSIONS: The overall prevalence of AMR reported by Euro-GASP reflects closely the AMR situation for N. gonorrhoeae in the EU/EEA. Euro-GASP data can be used to provide robust AMR estimates to inform the European guideline for the management of gonorrhoea.

Prescription and non-prescription antibiotic dispensing practices in part I and part II pharmacies in Moshi Municipality, Kilimanjaro Region in Tanzania: A simulated clients approach.

Antibiotic dispensing without a prescription poses a threat to public health as it leads to excessive antibiotic consumption. Inappropriate antibiotic availability to the community has been documented to be amongst drivers of antimicrobial resistance emergence. Community pharmacies are a source of antibiotics in low and middle-income countries (LMICs). We aimed at assessing antibiotic dispensing practices by community pharmacy retailers in Moshi urban, Kilimanjaro, Tanzania and recommend interventions to improve practice. Using a Simulated Client (SC) Method, an observational cross-sectional survey of antibiotic dispensing practices was conducted from 10th June to 10th July 2017. Data analysis was done using Stata 13 (StataCorp, College Station, TX, USA). A total of 82 pharmacies were visited. Part I pharmacies were 26 (31.71%) and 56 (68.29%) were part II. Overall 92.3% (95% CI 77.8-97.6) of retailers dispensed antibiotics without prescriptions. The antibiotics most commonly dispensed without a prescription were ampiclox for cough (3 encounters) and azithromycin for painful urination (3 encounters). An oral third generation cephalosporin (cefixime) was dispensed once for painful urination without prescription by a part I pharmacy retailer. Out of 21, 15(71.43%) prescriptions with incomplete doses were accepted and had antibiotics dispensed. Out of 68, 4(5.9%) retailers gave instructions for medicine use voluntarily. None of the retailers voluntarily explained drug side-effects. In Moshi pharmacies, a high proportion of antibiotics are sold and dispensed without prescriptions. Instructions for medicine use are rarely given and none of the retailers explain side effects. These findings support the need for a legislative enforcement of prescription-only antibiotic dispensing rules and regulations. Initiation of clinician and community antibiotic stewardship and educational programs on proper antibiotic use to both pharmacists and public by the regulatory bodies are highly needed.

Estimating the fitness cost and benefit of cefixime resistance in Neisseria gonorrhoeae to inform prescription policy: A modelling study.

BACKGROUND: Gonorrhoea is one of the most common bacterial sexually transmitted infections in England. Over 41,000 cases were recorded in 2015, more than half of which occurred in men who have sex with men (MSM). As the bacterium has developed resistance to each first-line antibiotic in turn, we need an improved understanding of fitness benefits and costs of antibiotic resistance to inform control policy and planning. Cefixime was recommended as a single-dose treatment for gonorrhoea from 2005 to 2010, during which time resistance increased, and subsequently declined. METHODS AND FINDINGS: We developed a stochastic compartmental model representing the natural history and transmission of cefixime-sensitive and cefixime-resistant strains of Neisseria gonorrhoeae in MSM in England, which was applied to data on diagnoses and prescriptions between 2008 and 2015. We estimated that asymptomatic carriers play a crucial role in overall transmission dynamics, with 37% (95% credible interval CrI 24%-52%) of infections remaining asymptomatic and untreated, accounting for 89% (95% CrI 82%-93%) of onward transmission. The fitness cost of cefixime resistance in the absence of cefixime usage was estimated to be such that the number of secondary infections caused by resistant strains is only about half as much as for the susceptible strains, which is insufficient to maintain persistence. However, we estimated that treatment of cefixime-resistant strains with cefixime was unsuccessful in 83% (95% CrI 53%-99%) of cases, representing a fitness benefit of resistance. This benefit was large enough to counterbalance the fitness cost when 31% (95% CrI 26%-36%) of cases were treated with cefixime, and when more than 55% (95% CrI 44%-66%) of cases were treated with cefixime, the resistant strain had a net fitness advantage over the susceptible strain. Limitations include sparse data leading to large intervals on key model parameters and necessary assumptions in the modelling of a complex epidemiological process. CONCLUSIONS: Our study provides, to our knowledge, the first estimates of the fitness cost and benefit associated with resistance of the gonococcus to a clinically relevant antibiotic. Our findings have important implications for antibiotic stewardship and public health policies and, in particular, suggest that a previously abandoned antibiotic could be used again to treat a minority of gonorrhoea cases without raising resistance levels.

Does the '2012 IUSTI ECCG report on the diagnosis and management of Neisseria gonorrhoeae infections in Europe' depict the situation in Europe?

Gonorrhoea is a major public health concern globally. Of particular grave concern is that resistance to the third generation cephalosporins has been identified during recent years. This paper summarises and discusses the results of the '2012 IUSTI European Collaborative Clinical Group (ECCG) report on the diagnosis and management of Neisseria gonorrhoeae infections in Europe'. Although high quality care was reported in many settings, in several other countries the testing, diagnostics, antimicrobial treatment and follow-up of gonorrhoea patients need to be optimized. This, together with increased access to and use of antimicrobial susceptibility testing, is crucial in controlling the emergent spread of cephalosporin-resistant and multidrug-resistant gonorrhoea.

Pelvic inflammatory disease in adolescents: care delivery in pediatric ambulatory settings.

OBJECTIVES: To evaluate care delivery patterns in patients treated for pelvic inflammatory disease in pediatric outpatient settings and to determine the effect of practice type on care delivery. DESIGN/SETTING: Retrospective review of medical records for patients treated as outpatients in an urban academic pediatric facility. Care patterns were evaluated according to the Centers for Disease Control sexually transmitted disease guidelines. PARTICIPANTS: Fifty-six adolescent patients who were diagnosed with pelvic inflammatory disease in pediatric ambulatory settings between January 1, 2002, and December 31, 2002. MAIN OUTCOME MEASURES: Demographic information, documented patient history and examination, laboratory data, and discharge instructions. RESULTS: Forty percent of patients were prescribed inadequate courses of medications. Patients who were seen in the pediatric emergency department were less likely to receive a standard medication regimen than those seen in the ambulatory setting. Most patients did not receive adequate instruction for self-care on review of written discharge instructions, and there were no differences based on location of care. CONCLUSIONS: Many adolescents treated as outpatients for pelvic inflammatory disease may not receive adequate medications and instructions for self-care at discharge in pediatric ambulatory settings. This study suggests a need for aggressive quality improvement measures to enhance the care of adolescents with pelvic inflammatory disease in pediatric outpatient settings.

[Direct costs to primary care of chronic bronchitis. Analysis of a prospective study]. / Costes directos de la bronquitis crónica en atención rimaria. Análisis de un estudio prospectivo.

OBJECTIVE: To evaluate the consumption of the direct health resources of primary care (PC) in Spain by a cohort of patients with chronic bronchial pathology: chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD). DESIGN: Prospective cohort study of patients with CB and COPD monitored in PC in Spain. The first 10 adult patients who attended at random each researcher's clinic and who were diagnosed as suffering an exacerbation of their chronic bronchial pathology were included. Scheduled follow-up visits for a year evaluated the cohort's consumption of health resources. Direct health costs were analysed. RESULTS: 268 doctors, with 2414 patients, took part. 1510 patients completed the 12 months follow-up (62.6%). All the patients received pharmacological treatment for their pulmonary disease. The most common complementary investigations performed were: general blood analysis (1.5 per patient/year), chest x-ray (1.2) and ECG (0.9), followed by spirometry (0.5) and arterial gasometry (0.4). Mean number of exacerbations per year were 1.9; and admissions, 0.2. Overall cost, including tests, medical visits, hospital expenditure and pharmacological treatment, was 420,264,000 pesetas for the entire cohort. The direct annual cost per patient ran at 278,321 pesetas. The cost caused by patients treated with Cefixime on the first exacerbations was 77,365 pesetas less, which was mostly due to less hospital expense. CONCLUSIONS: The direct annual cost per patient with CB or COPD is high, above the cost of other chronic respiratory pathologies such as bronchial asthma. There are notably greater hospital costs for CB and COPD, explained by these patients' mean greater age and the non-reversible and progressive deterioration of their respiratory function.

Cost-effectiveness of management strategies for acute urethritis in the developing world.

OBJECTIVE: To recommend a cost-effective approach for the management of acute male urethritis in the developing world, based on the findings of a theoretical study. METHODS: A model was developed to assess the cost-effectiveness of three urethritis management strategies in a theoretical cohort of 1000 men with urethral syndrome. (1) All patients were treated with cefixime and doxycycline for gonococcal urethritis (GU) and nongonococcal urethritis (NGU), respectively, as recommended by WHO. (2) All patients were treated with doxycycline for NGU; treatment with cefixime was based on the result of direct microscopy of a urethral smear. (3) All patients were treated with cotrimoxazole or kanamycin for GU and doxycycline for NGU. Cefixime was kept for patients not responding to the first GU treatment. Strategy costs included consultations, laboratory diagnosis (where applicable) and drugs. The outcome was the rate of patients cured of urethritis. Cost-effectiveness was measured in terms of cost per cured urethritis. RESULTS: Strategy costs in our model depended largely on drug costs. The first strategy was confirmed as the most effective but also the most expensive approach. Cefixime should cost no more than US$ 1.5 for the strategy to be the most cost-effective. The second strategy saved money and drugs but proved a valuable alternative only when laboratory performance was optimal. The third strategy with cotrimoxazole was the least expensive but a low follow-up visit rate, poor treatment compliance or lower drug efficacy limited effectiveness. Maximizing compliance by replacing cotrimoxazole with single-dose kanamycin had the single greatest impact on the effectiveness of the third strategy. CONCLUSION: Our model suggested that a cost-effective approach would be to treat gonorrhoea with a single-dose antibiotic selected from locally available products that cost no more than US$ 1.5.

Sequential antimicrobial therapy: treatment of severe lower respiratory tract infections in children.

Although there have been a number of studies in adults, to date there has been little research into sequential antimicrobial therapy (SAT) in paediatric populations. The present study evaluates the impact of a SAT protocol for the treatment of severe lower respiratory tract infection in paediatric patients. The study involved 89 paediatric patients (44 control and 45 SAT). The SAT patients had a shorter length of hospital stay (4.0 versus 8.3 days), shorter duration of inpatient antimicrobial therapy (4.0 versus 7.9 days) with the period of iv therapy being reduced from a mean of 5.6 to 1.7 days. The total healthcare costs were reduced by 52%. The resolution of severe lower respiratory tract infection with a short course of iv antimicrobials, followed by conversion to oral therapy yielded clinical outcomes comparable to those achieved using longer term iv therapy. SAT proved to be an important cost-minimizing tool for realizing substantial healthcare costs savings.