Nationwide upsurge in invasive disease in the context of longitudinal surveillance of carriage and invasive Streptococcus pyogenes 2009-2023, the Netherlands: a molecular epidemiological study.

Since 2022, many countries have reported an upsurge in invasive group A streptococcal (iGAS) infections. We explored whether changes in Streptococcus pyogenes carriage rates or emergence of strains with potentially altered virulence, such as emm1 variants M1UK and M1DK, contributed to the 2022/2023 surge in the Netherlands. We determined emm (sub)type distribution for 2,698 invasive and 351 S. pyogenes carriage isolates collected between January 2009 and March 2023. Genetic evolution of emm1 was analyzed by whole-genome sequencing of 497 emm1 isolates. The nationwide iGAS upsurge coincided with a sharp increase of emm1.0 from 18% (18/100) of invasive isolates in Q1 2022 to 58% (388/670) in Q1 2023 (Fisher's exact test, P < 0.0001). M1UK became dominant among invasive emm1 isolates in 2016 and further expanded from 72% in Q1 2022 to 96% in Q1 2023. Phylogenetic comparison revealed evolution and clonal expansion of four new M1UK clades in 2022/2023. DNase Spd1 and superantigen SpeC were acquired in 9% (46/497) of emm1 isolates. S. pyogenes carriage rates and emm1 proportions in carriage isolates remained stable during this surge, and the expansion of M1UK in iGAS was not reflected in carriage isolates. During the 2022/2023 iGAS surge in the Netherlands, expansion of four new M1UK clades was observed among invasive isolates, but not carriage isolates, suggesting increased virulence and fitness of M1UK compared to contemporary M1 strains. The emergence of more virulent clades has important implications for public health strategies such as antibiotic prophylaxis for close contacts of iGAS patients.IMPORTANCEThis study describes the molecular epidemiology of invasive group A streptococcal (iGAS) infections in the Netherlands based on >3,000 Streptococcus pyogenes isolates from both asymptomatic carriers and iGAS patients collected before, during, and after the COVID-19 pandemic period (2009-2023) and is the first to assess whether changes in carriage rates or carried emm types contributed to the alarming post-COVID-19 upsurge in iGAS infections. We show that the 2022/2023 iGAS surge coincided with a sharp increase of emm1, particularly the toxicogenic M1UK variant, in invasive isolates, but not in carriage isolates. These findings suggest that increased virulence and fitness of M1UK likely contributes to an increased dissemination between hosts. The emergence of a more virulent and fit lineage has important implications for iGAS control interventions such as antibiotic prophylaxis for close contacts of iGAS patients and calls for a reappraisal of iGAS control interventions and guidelines.

Novel emm4 lineage associated with an upsurge in invasive group A streptococcal disease in the Netherlands, 2022.

Invasive group A streptococcal (iGAS) disease cases increased in the first half of 2022 in the Netherlands, with a remarkably high proportion of emm4 isolates. Whole-genome sequence analysis of 66 emm4 isolates, 40 isolates from the pre-coronavirus disease 2019 (COVID-19) pandemic period 2009-2019 and 26 contemporary isolates from 2022, identified a novel Streptococcus pyogenes lineage (M4NL22), which accounted for 85 % of emm4 iGAS cases in 2022. Surprisingly, we detected few isolates of the emm4 hypervirulent clone, which has replaced nearly all other emm4 in the USA and the UK. M4NL22 displayed genetic differences compared to other emm4 strains, although these were of unclear biological significance. In publicly available data, we identified a single Norwegian isolate belonging to M4NL22, which was sampled after the isolates from this study, possibly suggesting export of M4NL22 to Norway. In conclusion, our study identified a novel S. pyogenes emm4 lineage underlying an increase of iGAS disease in early 2022 in the Netherlands and the results have been promptly communicated to public health officials.

Group A Streptococcal Meningitis With the M1UK Variant in the Netherlands.

This study reports an epidemiological assessment of laboratory-confirmed group A streptococcal meningitis cases in the Netherlands using more than 40 years of national bacteriological surveillance data.

[Invasive group A streptococcal infections in the Netherlands]. / Invasieve groep A-streptokokkeninfecties in Nederland.

Group A streptococcal (GAS) infections are caused by the Gram-positive bacterium Streptococcus pyogenes. Infection can occur via droplet infection from the throat and via (in)direct contact with infected people. GAS can cause a wide variety of diseases, ranging from superficial skin infections, pharyngitis and scarlet fever, to serious invasive diseases such as puerperal sepsis, pneumonia, necrotising soft tissue infections (NSTI) (also known as necrotising fasciitis/myositis), meningitis and streptococcal toxic shock syndrome (STSS). In invasive GAS infections, the bacteria has penetrated into a sterile body compartment (such as the bloodstream, deep tissues, or the central nervous system). Invasive GAS infections are rare but serious, with high morbidity and mortality. Since March 2022, the National Institute for Public Health and the Environment (RIVM) reported a national increase in notifiable invasive GAS infections (NSTI, STSS and puerperal fever). Particularly NSTI has increased compared to the years before the SARS-CoV-2 pandemic. Remarkably, the proportion of children aged 0 to 5 years with invasive GAS-infections is higher in 2022 than in the previous years (12% compared to 4%). While seasonal peaks occur, the current elevation exceeds this variation. To promote early recognition and diagnosis of invasive GAS infections different clinical cases are presented.

Increase in Invasive Group a Streptococcal Infections in Children in the Netherlands, A Survey Among 7 Hospitals in 2022.

Following an increase in notifiable invasive group A streptococcal (iGAS) infections in the Netherlands, we conducted a survey among 7 hospitals. Pediatric iGAS case numbers were 2-fold higher between July 2021 and June 2022 versus pre-COVID-19. A sharp increase occurred early 2022, most pronounced in <5 years old and for diagnoses empyema and necrotizing fasciitis. This recent pediatric iGAS surge warrants investigation and vigilance.

The dynamics of scarlet fever in The Netherlands, 1906-1920: a historical analysis.

Background. Scarlet fever, an infectious disease caused by Streptococcus pyogenes, largely disappeared in developed countries during the twentieth century. In recent years, scarlet fever is on the rise again, and there is a need for a better understanding of possible factors driving transmission. Methods. Using historical case notification data from the three largest cities in The Netherlands (Amsterdam, Rotterdam and The Hague) from 1906 to 1920, we inferred the transmission rate for scarlet fever using time-series susceptible-infected-recovered (TSIR) methods. Through additive regression modelling, we investigated the contributions of meteorological variables and school term times to transmission rates. Results. Estimated transmission rates varied by city, and were highest overall for Rotterdam, the most densely populated city at that time. High temperature, seasonal precipitation levels and school term timing were associated with transmission rates, but the roles of these factors were limited and not consistent over all three cities. Conclusions. While weather factors alone can only explain a small portion of the variability in transmission rates, these results help understand the historical dynamics of scarlet fever infection in an era with less advanced sanitation and no antibiotic treatment and may offer insights into the driving factors associated with its recent resurgence.

Antibiotic prophylaxis for acute cholecystectomy: PEANUTS II multicentre randomized non-inferiority clinical trial.

BACKGROUND: Guidelines recommending antibiotic prophylaxis at emergency cholecystectomy for cholecystitis were based on low-quality evidence. The aim of this trial was to demonstrate that omitting antibiotics is not inferior to their prophylactic use. METHODS: This multicentre, randomized, open-label, non-inferiority clinical trial randomly assigned adults with mild-to-moderate acute calculous cholecystitis (immediate cholecystectomy indicated) to 2 g cefazolin administered before incision or no antibiotic prophylaxis. The primary endpoint was a composite of all postoperative infectious complications in the first 30 days after surgery. Secondary endpoints included all individual components of the primary endpoint, other morbidity, and duration of hospital stay. RESULTS: Sixteen of 226 patients (7.1 per cent) in the single-dose prophylaxis group and 29 of 231 (12.6 per cent) in the no-prophylaxis group developed postoperative infectious complications (absolute difference 5.5 (95 per cent c.i. -0.4 to 11.3) per cent). With a non-inferiority margin of 10 per cent, non-inferiority of no prophylaxis was not proven. The number of surgical-site infections was significantly higher in the no-prophylaxis group (5.3 versus 12.1 per cent; P = 0.010). No differences were observed in the number of other complications, or duration of hospital stay. CONCLUSION: Omitting antibiotic prophylaxis is not recommended.

First autochthonous human West Nile virus infections in the Netherlands, July to August 2020.

In October 2020, the first case of autochthonous West Nile virus neuroinvasive disease was diagnosed in the Netherlands with a presumed infection in the last week of August. Investigations revealed five more cases of local West Nile virus (WNV) infection. The cases resided in a region where WNV was detected in a bird and mosquitoes in August 2020. Molecular analysis was successful for two cases and identified the presence of WNV lineage 2.

The burden of bacteremic and non-bacteremic Gram-negative infections: A prospective multicenter cohort study in a low-resistance country.

Objectives There is a global increase in infections caused by Gram-negative bacteria. The majority of research is on bacteremic Gram-negative infections (GNI), leaving a knowledge gap on the burden of non-bacteremic GNI. Our aim is to describe characteristics and determine the burden of bacteremic and non-bacteremic GNI in hospitalized patients in the Netherlands. Methods We conducted a prospective cohort study of patients in eight hospitals with microbiologically confirmed GNI, between June 2013 and November 2015. In each hospital the first five adults meeting the eligibility criteria per week were enrolled. We estimated the national incidence and mortality of GNI by combining the cohort data with a national surveillance database for antimicrobial resistance. Results 1,954 patients with GNI were included of which 758 (39%) were bloodstream infections (BSI). 243 GNI (12%) involved multi-drug resistant pathogens. 30-day mortality rate was 11.1% (n = 217) Estimated national incidences of non-bacteremic GNI and bacteremic GNI in hospitalized adults were 74 (95% CI 58 - 89) and 86 (95% CI 72-100) per 100,000 person years, yielding estimated annual numbers of 30-day all-cause mortality deaths of 1,528 (95% CI 1,102-1,954) for bacteremic and 982 (95% CI 688 - 1,276) for non-bacteremic GNI. Conclusion GNI form a large mortality burden in a low-resistance country. A third of the associated mortality occurs after non-bacteremic GNI.

Attributable mortality of antibiotic resistance in gram-negative infections in the Netherlands: a parallel matched cohort study.

OBJECTIVES: Antibiotic resistance in Gram-negative bacteria has been associated with increased mortality. This was demonstrated mostly for third-generation cephalosporin-resistant (3GC-R) Enterobacterales bacteraemia in international studies. Yet, the burden of resistance specifically in the Netherlands and created by all types of Gram-negative infection has not been quantified. We therefore investigated the attributable mortality of antibiotic resistance in Gram-negative infections in the Netherlands. METHODS: In eight hospitals, a sample of Gram-negative infections was identified between 2013 and 2016, and separated into resistant and susceptible infection cohorts. Both cohorts were matched 1:1 to non-infected control patients on hospital, length of stay at infection onset, and age. In this parallel matched cohort set-up, 30-day mortality was compared between infected and non-infected patients. The impact of resistance was then assessed by dividing the two separate risk ratios (RRs) for mortality attributable to Gram-negative infection. RESULTS: We identified 1954 Gram-negative infections, of which 1190 (61%) involved Escherichia coli, 210 (11%) Pseudomonas aeruginosa, and 758 (39%) bacteraemia. Resistant Gram-negatives caused 243 infections (12%; 189 (78%) 3GC-R Enterobacterales, nine (4%) multidrug-resistant P. aeruginosa, no carbapenemase-producing Enterobacterales). Subsequently, we matched 1941 non-infected controls. After adjustment, point estimates for RRs comparing mortality between infections and controls were similarly higher than 1 in case of resistant infections and susceptible infections (1.42 (95% confidence interval 0.66-3.09) and 1.32 (1.06-1.65), respectively). By dividing these, the RR reflecting attributable mortality of resistance was calculated as 1.08 (0.48-2.41). CONCLUSIONS: In the Netherlands, antibiotic resistance did not increase 30-day mortality in Gram-negative infections.

Prevention of severe infectious complications after colorectal surgery using oral non-absorbable antimicrobial prophylaxis: results of a multicenter randomized placebo-controlled clinical trial.

BACKGROUND: Surgical site infections (SSIs) are common complications after colorectal surgery. Oral non-absorbable antibiotic prophylaxis (OAP) can be administered preoperatively to reduce the risk of SSIs. Its efficacy without simultaneous mechanical cleaning is unknown. METHODS: The Precaution trial was a double-blind, placebo-controlled randomized clinical trial conducted in six Dutch hospitals. Adult patients who underwent elective colorectal surgery were randomized to receive either a three-day course of preoperative OAP with tobramycin and colistin or placebo. The primary composite endpoint was the incidence of deep SSI or mortality within 30 days after surgery. Secondary endpoints included both infectious and non-infectious complications at 30 days and six months after surgery. RESULTS: The study was prematurely ended due to the loss of clinical equipoise. At that time, 39 patients had been randomized to active OAP and 39 to placebo, which reflected 8.1% of the initially pursued sample size. Nine (11.5%) patients developed the primary outcome, of whom four had been randomized to OAP (4/39; 10.3%) and five to placebo (5/39; 12.8%). This corresponds to a risk ratio in the intention-to-treat analysis of 0.80 (95% confidence interval (CI) 0.23-2.78). In the per-protocol analysis, the relative risk was 0.64 (95% CI 0.12-3.46). CONCLUSIONS: Observational data emerging during the study provided new evidence for the effectiveness of OAP that changed both the clinical and medical ethical landscape for infection prevention in colorectal surgery. We therefore consider it unethical to continue randomizing patients to placebo. We recommend the implementation of OAP in clinical practice and continuing monitoring of infection rates and antibiotic susceptibilities. TRIAL REGISTRATION: The PreCaution trial is registered in the Netherlands Trial Register under NL5932 (previously: NTR6113) as well as in the EudraCT register under 2015-005736-17.

Twelve years of pneumococcal conjugate vaccination in the Netherlands: Impact on incidence and clinical outcomes of invasive pneumococcal disease.

INTRODUCTION: In 2006, the Netherlands introduced the 7-valent pneumococcal conjugate vaccine (PCV7) in their national immunisation programme. In 2011, PCV7 was replaced by the 10-valent vaccine (PCV10). We report on the impact of PCV on invasive pneumococcal disease (IPD) incidence, clinical syndromes and patient outcomes. METHODS: Pneumococcal isolates of hospitalised IPD patients between June 2004 and May 2018 were obtained from nine sentinel laboratories, covering 25% of the Dutch population. All isolates were serotyped. IPD incidence and clinical outcome were determined before and after introduction of PCV7 and after the switch to PCV10, stratified by age and serotype. RESULTS: Compared to before PCV7 introduction, significant declines in IPD incidence were observed in 2016-2018 in children <5 years (69%), 18-49 year olds (31%) and ≥65 year olds (19%). Compared to before PCV10 introduction, the IPD incidence in 2016-2018 declined in children <5 years (RR:0.68, 95%CI:0.42-1.11), 5-17 year olds (RR:0.58, 95%CI:0.29-1.14) and 18-49 year olds (RR:0.72, 95%CI:0.57-0.90), but not in 50-64 year olds (RR:0.94, 95%CI:0.81-1.10) and ≥65 year olds (RR:1.04, 95%CI:0.0.93-1.15). While the case fatality rate (CFR) decreased from 16.2% pre-PCV to 13.4% post-PCV10 (RR:0.83, 95%CI:0.70-0.99), the switch to PCV10 had no further impact on CFR (RR:1.14, 95%CI:0.96-1.36). CONCLUSION: Twelve years of PCV in the Netherlands has resulted in a sustained reduction of IPD incidence in children and younger adults. The switch from PCV7 to PCV10 did not have additional impact on the IPD incidence in older adults and CFR due to emerging non-vaccine serotypes.

Associations between common respiratory viruses and invasive group A streptococcal infection: A time-series analysis.

BACKGROUND: Invasive infections by group A Streptococcus (iGAS, Streptococcus pyogenes) have a winter seasonality which largely coincides with the season for influenza and other respiratory viruses. Influenza superinfections with GAS have been described to occur regularly and to show a severe clinical picture with high mortality. We aimed to study the extent to which influenza A and B viruses (IAV and IBV), respiratory syncytial virus (RSV) and rhinovirus circulation contribute to iGAS incidence and severity. METHODS: Time-series regression models were built to explore the temporal associations between weekly laboratory counts of IAV, IBV, RSV and rhinovirus as independent variables and weekly counts of GAS disease notifications or laboratory GAS cultures as dependent variables. RESULTS: The weekly number of IAV detections showed a significant temporal association with the number of notifications of streptococcal toxic shock syndrome (STSS), a severe complication of iGAS. Depending on the season, up to 40% of all notified STSS cases was attributable to IAV circulation. Besides STSS, none of the other iGAS manifestations were associated with a respiratory virus. CONCLUSIONS: Our study found an ecological temporal association between IAV and STSS, the most severe complication of iGAS. Future studies are needed to confirm this association and assess the possible preventability of STSS by influenza vaccination, especially in the age group 60 years and older.

The extent of microbiological testing is associated with alteration of antibiotic therapy in adults with community-acquired pneumonia.

The aim of this study was to explore the relationship between the extent of microbiological testing and the frequency of antibiotic alteration in adults hospitalised with community-acquired pneumonia (CAP). We retrospectively studied 283 immunocompetent patients hospitalised with CAP. Information on microbiological testing and prescribed antibiotics was obtained. Patients were grouped according to the number of different microbiological tests performed within the first 2 days of admission (0-5 tests). Alteration rates were compared between these groups. Antimicrobial alteration was defined as a switch at day 3 of hospital stay to (1) a narrower spectrum antibiotics, or (2) a different class of antibiotics, or (3) a switch from dual therapy to monotherapy (4) or discontinuation of antibiotic treatment because the indication for antibiotic treatment did no longer exist. For each additional test performed, a stepwise increase in percentage of patients with altered antibiotic regimen ranging from 0 to 59% (p = 0.001) was found. Multivariate logistic regression analyses showed that performing PCR assay for atypical pathogens was most strongly associated with any alteration of antibiotic treatment (OR 2.6 (95% CI 1.4-4.9)) and with changes in atypical coverage specifically (OR 3.1 (95% CI 1.6-6.0). The extent of microbiological testing was positively associated with antibiotic alteration in adults hospitalised with CAP. Antibiotic treatment was most likely to be altered in patients in whom PCR assay for atypical pathogens was performed.

Exhaustion of the immune system by Group A Streptococcus necrotizing fasciitis: the occurrence of late secondary infections in a retrospective study.

BACKGROUND: Necrotizing fasciitis is a potentially lethal condition for which early and adequate treatment with surgical debridement and broad-spectrum intravenous antibiotics are essential for survival. It is hypothesized that Group A Streptococcus (GAS) necrotizing fasciitis causes exhaustion of the immune system, making these patients more susceptible for late secondary infections. METHODS: A retrospective study was conducted of all patients with necrotizing fasciitis between 2002 and 2016. Patients with necrotizing fasciitis based on macroscopic findings, positive Gram staining, culture or fresh frozen section of fascia biopsies were included. Patients with necrotizing fasciitis were divided into two groups based on the presence of GAS. Of both groups, clinical course, outcome and occurrence of late secondary infections were analyzed. For the occurrence of secondary infections, pneumonia was chosen as reference for late secondary infections. RESULTS: Eighty-one patients with necrotizing fasciitis were included of which 38 (47%) had GAS necrotizing fasciitis and 43 (53%) had non-GAS necrotizing fasciitis. Patients with GAS necrotizing fasciitis were younger (50 vs. 61 years, p=0.023) and more often classified as ASA I (45% vs. 14%, p=0.002) compared with patients with non-GAS necrotizing fasciitis. In-hospital mortality rate for necrotizing fasciitis was 32%. Patients with comorbidities were more likely to die of necrotizing fasciitis compared with patients without comorbidities (OR 7.41, 95% CI 1.58 to 34.63). Twelve patients (39%) with GAS necrotizing fasciitis developed pneumonia compared with four patients (13%) with non-GAS necrotizing fasciitis (p=0.017; OR 4.42, 95% CI 1.124 to 15.79). Median time from diagnosis to development of pneumonia in patients with GAS necrotizing fasciitis was 10 days (IQR 9). CONCLUSION: Patients with GAS necrotizing fasciitis have an increased risk to develop late secondary infections during initial treatment for necrotizing fasciitis compared with patients with necrotizing fasciitis without involvement of GAS. This suggests exhaustion of the immune system after severe GAS infection. LEVEL OF EVIDENCE: III.

REtrieval And cure of Chronic Hepatitis C (REACH): Results of micro-elimination in the Utrecht province.

BACKGROUND: The Netherlands is one of the six European countries considered on track to eliminate hepatitis C virus by 2030. To achieve this goal, continuous efforts have to be put into designing efficient case-finding strategies, including the retrieval of previously diagnosed hepatitis C virus-infected who are lost to follow-up. AIMS: To trace and treat all lost to follow-up hepatitis C virus patients in the Utrecht region and create an efficient retrieval strategy that can be used in future (national) retrieval initiatives. METHODS: Positive hepatitis C virus diagnostic tests (anti-hepatitis C virus IgG or hepatitis C virus-RNA) from the laboratory of all four hospitals and one central laboratory for primary care diagnostics in the province of Utrecht from 2001 to 2015 were linked to clinical records. Untreated patients with available contact information were deemed eligible for retrieval and invited for reevaluation with (virology) blood tests, fibroscan measurement and possible direct-acting antiviral therapy. MAIN RESULTS: After screening all hepatitis C virus diagnostics, 1913 chronic hepatitis C virus-infected were identified of which 14.1% (n = 269) were invited back into care. Overall, 17.4% was traced with the highest yield (28.3%) in those who lived in the Utrecht province. Through renewed patient assessments, 42 chronic hepatitis C virus infections were re-identified (76% with a history of intravenous drug use, 24% with Metavir F3-F4). Until now, 59% has either scheduled or initiated direct-acting antiviral therapy. CONCLUSION: The retrieval of previously diagnosed hepatitis C virus patients through screening of laboratory diagnostics from the past is feasible and should be pursued for further control and reduction of hepatitis C virus infection. Retrieval is most successful when performed regionally. LAY SUMMARY: To completely eliminate chronic hepatitis C virus (HCV) infection and prevent complications, undiagnosed and also previously diagnosed but lost to follow-up (LFU) HCV patients have to be brought (back) into care for therapy. Retrieval of LFU HCV patients through screening of laboratory diagnostics from the past is feasible and most successful when performed regionally.

Perioperative antibiotic prophylaxis in the treatment of acute cholecystitis (PEANUTS II trial): study protocol for a randomized controlled trial.

BACKGROUND: The additional value of perioperative antibiotic prophylaxis in preventing infectious complications after emergency cholecystectomy for acute cholecystitis is a much-debated subject in the surgical community. Evidence-based guidelines are lacking, and consequently the use of antibiotic prophylaxis varies greatly among surgeons and hospitals. Recently, high-level evidence became available demonstrating that postoperative antibiotic prophylaxis in patients with acute cholecystitis does not reduce the risk of infectious complications. Preoperative antibiotic prophylaxis in relation to the risk of infectious complications, however, has never been studied. METHODS: The PEANUTS II trial is a randomized, controlled, multicenter, open-label noninferiority trial whose aim is to determine the utility of preoperative antibiotic prophylaxis in patients undergoing emergency cholecystectomy for acute calculous cholecystitis. Patients with mild or moderate acute cholecystitis, as defined according the Tokyo Guidelines, will be randomly assigned to a single preoperative dose of antibiotic prophylaxis (2000 mg of first-generation cephalosporin delivered intravenously) or no antibiotic prophylaxis before emergency cholecystectomy. The primary endpoint is a composite endpoint consisting of all postoperative infectious complications occurring during the first 30 days after surgery. Secondary endpoints include all the individual components of the primary endpoint, all other complications, duration of hospital stay, and total costs. The hypothesis is that the absence of antibiotic prophylaxis is noninferior to the presence of antibiotic prophylaxis. A noninferiority margin of 10% is assumed. With a 1-sided risk of 2.5% and a power of 80%, a total of 454 subjects will have to be included. Analysis will be performed according to the intention-to-treat principle. DISCUSSION: The PEANUTS II trial will provide evidence-based advice concerning the utility of antibiotic prophylaxis in patients undergoing emergency cholecystectomy for acute calculous cholecystitis. TRIAL REGISTRATION: Netherlands Trial Register, NTR5802 . Registered on 4 June 2016.