Markedly decreasing azithromycin susceptibility of Neisseria gonorrhoeae, Germany, 2014 to 2021.

We monitored antimicrobial susceptibility developments of Neisseria gonorrhoeae in Germany from January 2014 to May 2021. The proportion of isolates with azithromycin minimum inhibitory concentrations above the epidemiological cut-off increased substantially, from 1.3% in 2014 to 12.2% in 2020. Preliminary data from 2021 showed a further rise (January to May: 20.7%). Therefore, azithromycin as part of the recommended dual therapy in Germany for non-adherent patients is challenged. Antimicrobial susceptibility testing in clinical practice is crucial and continuous susceptibility surveillance indispensable.

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.

Molecular epidemiological typing of Neisseria gonorrhoeae isolates identifies a novel association between genogroup G10557 (G7072) and decreased susceptibility to cefixime, Germany, 2014 to 2017.

BackgroundEmerging antimicrobial resistance (AMR) challenges gonorrhoea treatment and requires surveillance.AimThis observational study describes the genetic diversity of Neisseria gonorrhoeae isolates in Germany from 2014 to 2017 and identifies N. gonorrhoeae multi-antigen sequence typing (NG-MAST) genogroups associated with AMR or some patient demographics.Methods1,220 gonococcal isolates underwent AMR testing and NG-MAST. Associations between genogroups and AMR or sex/age of patients were statistically assessed.ResultsPatients' median age was 32 years (interquartile range: 25-44); 1,078 isolates (88.4%) originated from men. In total, 432 NG-MAST sequence types including 156 novel ones were identified, resulting in 17 major genogroups covering 59.1% (721/1,220) of all isolates. Genogroups G1407 and G10557 (G7072) were significantly associated with decreased susceptibility to cefixime (Kruskal-Wallis chi-squared: 549.3442, df: 16, p < 0.001). Their prevalences appeared to decline during the study period from 14.2% (15/106) to 6.2% (30/481) and from 6.6% (7/106) to 3.1% (15/481) respectively. Meanwhile, several cefixime susceptible genogroups' prevalence seemed to increase. Proportions of isolates from men differed among genogroups (Fisher's exact test, p < 0.001), being e.g. lower for G25 (G51) and G387, and higher for G5441 and G2992. Some genogroups differed relative to each other in affected patients' median age (Kruskal-Wallis chi-squared: 47.5358, df: 16, p < 0.001), with e.g. G25 (G51) and G387 more frequent among ≤ 30 year olds and G359 and G17420 among ≥ 40 year olds.ConclusionAMR monitoring with molecular typing is important. Dual therapy (ceftriaxone plus azithromycin) recommended in 2014 in Germany, or only the ceftriaxone dose of this therapy, might have contributed to cefixime-resistant genogroups decreasing.

A precise performance-based reimbursement model for the multi-centre NAPKON cohorts - development and evaluation.

Fair allocation of funding in multi-centre clinical studies is challenging. Models commonly used in Germany - the case fees ("fixed-rate model", FRM) and up-front staffing and consumables ("up-front allocation model", UFAM) lack transparency and fail to suitably accommodate variations in centre performance. We developed a performance-based reimbursement model (PBRM) with automated calculation of conducted activities and applied it to the cohorts of the National Pandemic Cohort Network (NAPKON) within the Network of University Medicine (NUM). The study protocol activities, which were derived from data management systems, underwent validation through standardized quality checks by multiple stakeholders. The PBRM output (first funding period) was compared among centres and cohorts, and the cost-efficiency of the models was evaluated. Cases per centre varied from one to 164. The mean case reimbursement differed among the cohorts (1173.21€ [95% CI 645.68-1700.73] to 3863.43€ [95% CI 1468.89-6257.96]) and centres and mostly fell short of the expected amount. Model comparisons revealed higher cost-efficiency of the PBRM compared to FRM and UFAM, especially for low recruitment outliers. In conclusion, we have developed a reimbursement model that is transparent, accurate, and flexible. In multi-centre collaborations where heterogeneity between centres is expected, a PBRM could be used as a model to address performance discrepancies.Trial registration: https://clinicaltrials.gov/ct2/show/NCT04768998 ; https://clinicaltrials.gov/ct2/show/NCT04747366 ; https://clinicaltrials.gov/ct2/show/NCT04679584 .

The usefulness of C-reactive protein in predicting malaria parasitemia in a sub-Saharan African region.

BACKGROUND: Malaria remains a leading cause of childhood mortality in sub-Saharan Africa. Identifying patients who are at risk for severe manifestations at presentation still remains challenging. This study examines whether a semi-quantitative test on C-Reactive Protein (CRP) could be useful for rapidly predicting the presence or absence of malarial parasitemia in febrile children. METHOD: Data were collected from children with fever or a history of fever at the Agogo Presbyterian Hospital in the Ashanti Region of Ghana. Haematological measurements, microscopic detection of plasmodium species and semi-quantitative CRP measurements with a membrane-based immunoassay for whole blood were performed. CRP was classified as positive when the measured level was ≥ 10 mg/l. RESULTS: During 548 visits, thick blood film results could be obtained from 541 patients, 270 (49.3%) yielded parasitemia with Plasmodium spp. Whereas malaria parasites were detected in only a few patients (7.1%) with normal CRP levels (< 10mg/l), more than a half of patients with an increased CRP concentration (≥ 10 mg/l) were parasite positive (OR 14.5 [CI 4.4-47.6], p<0.001). Patients with increased CRP levels had more than an eight-fold likelihood for parasitemia after correction for other parameters (adjusted OR 8.7 [CI 2.5-30.5], p<0.001). Sensitivity, specificity as well as positive predictive and negative predictive values of CRP for malaria were 99.3% (CI 96.2%-100%), 9.2% (CI 6.4%-12.8%), 31.7% (CI 27.4%-36.1%) and 97.0% (CI 84.2%-99.9%), respectively. CONCLUSION: The semi-quantitative method of measuring CRP is cheap, rapid and easy to perform but not useful in predicting parasitemia and malaria. However, due to its high negative predictive value, it could have a role in identifying those patients unlikely to be presenting with clinical malaria.