Narrow-spectrum antibiotics for community-acquired pneumonia in Dutch adults (CAP-PACT): a cross-sectional, stepped-wedge, cluster-randomised, non-inferiority, antimicrobial stewardship intervention trial.

BACKGROUND: Adults hospitalised to a non-intensive care unit (ICU) ward with moderately severe community-acquired pneumonia are frequently treated with broad-spectrum antibiotics, despite Dutch guidelines recommending narrow-spectrum antibiotics. Therefore, we investigated whether an antibiotic stewardship intervention would reduce the use of broad-spectrum antibiotics in patients with moderately severe community-acquired pneumonia without compromising their safety. METHODS: In this cross-sectional, stepped-wedge, cluster-randomised, non-inferiority trial (CAP-PACT) done in 12 hospitals in the Netherlands, we enrolled immunocompetent adults (≥18 years) who were admitted to a non-ICU ward and had a working diagnosis of moderately severe community-acquired pneumonia. All participating hospitals started in a control period and every 3 months a block of two hospitals transitioned from the control to the intervention period, with all hospitals eventually ending in the intervention period. The unit of randomisation was the hospital (cluster), and electronic randomisation (by an independent data manager) decided the sequence (the time of intervention) by which hospitals would cross over from the control period to the intervention period. Blinding was not possible. The antimicrobial stewardship intervention was a bundle targeting health-care providers and comprised education, engaging opinion leaders, and prospective audit and feedback of antibiotic use. The co-primary outcomes were broad-spectrum days of therapy per patient, tested by superiority, and 90-day all-cause mortality, tested by non-inferiority with a non-inferiority margin of 3%, and were analysed in the intention-to-treat population, comprising all patients who were enrolled in the control and intervention periods. This trial was prospectively registered at ClinicalTrials.gov, NCT02604628. FINDINGS: Between Nov 1, 2015, and Nov 1, 2017, 5683 patients were assessed for eligibility, of whom 4084 (2235 in the control period and 1849 in the intervention period) were included in the intention-to-treat analysis. The adjusted mean broad-spectrum days of therapy per patient were reduced from 6·5 days in the control period to 4·8 days in the intervention period, yielding an absolute reduction of -1·7 days (95% CI -2·4 to -1·1) and a relative reduction of 26·6% (95% CI 18·0-35·3). Crude 90-day mortality was 10·9% (242 of 2228 died) in the control period and 10·8% (199 of 1841) in the intervention period, yielding an adjusted absolute risk difference of 0·4% (90% CI -2·7 to 2·4), indicating non-inferiority. INTERPRETATION: In patients hospitalised with moderately severe community-acquired pneumonia, a multifaceted antibiotic stewardship intervention might safely reduce broad-spectrum antibiotic use. FUNDING: None.

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.

Risk-based maternal group B Streptococcus screening strategy is compatible with the implementation of neonatal early-onset sepsis calculator.

BACKGROUND: The early-onset sepsis (EOS) calculator was developed and validated in a setting with routine-based group B Streptococcus (GBS) screening. PURPOSE: The study aimed to evaluate the extent of influence exerted by risk-based GBS screening on management recommendations by the EOS calculator. METHODS: All newborns with a gestational age greater than 35 weeks were screened for EOS risk factors in a Dutch regional teaching hospital using a risk-based GBS screening strategy. We calculated the EOS risk at birth and stratified the infants into the following 3 risk levels with corresponding management recommendations: low, <0.65; intermediate, 0.65-1.54; and high, >1.54 per 1000 live newborns. Thereafter, we recalculated the EOS risk and recommendation for the newborn infants without available maternal GBS screening results at birth. RESULTS: In one year, 1,877 eligible births occurred; of them, 206 infants were included. Maternal GBS status was available for 28 of 206 infants (14%) at birth, while a definitive GBS status was later available for 162 of 206 infants (79%). Median EOS risk was slightly lower after definitive GBS status was determined (0.41 vs. 0.46 per 1,000 live births, P=0.004). In 199 of 206 newborn infants (97%), the EOS calculator recommendation remained unchanged after the GBS results unavailable at birth were updated to definitive GBS status. Use of GBS status at birth versus definitive GBS status did not result in the withholding of antibiotic treatment of the newborn infants included in this study. CONCLUSION: Risk-based GBS screening is compatible with EOS calculator recommendations. Larger studies are needed to develop the best strategy for combining GBS screening and EOS calculator recommendations.

Primary Epstein-Barr virus infection in immunocompetent patients with acute transverse myelitis and a combination of polyradiculitis and anterior horn syndrome as neurological manifestations.

Neurological manifestations of a primary Epstein-Barr virus (EBV) infection are rare. We describe a case with acute transverse myelitis and another case with a combination of polyradiculitis and anterior horn syndrome as manifestations of a primary EBV infection.The first case is a 50-year-old immunocompetent male diagnosed with acute transverse myelitis, 2 weeks after he was clinically diagnosed with infectious mononucleosis. The second case is an 18-year-old immunocompetent male diagnosed with a combination of polyradiculitis and anterior horn syndrome while he had infectious mononucleosis. The first patient was treated with methylprednisolone. After 1 year, he was able to stop performing clean intermittent self-catheterisation. The second patient completely recovered within 6 weeks without treatment.Primary EBV infection should be considered in immunocompetent patients presenting with acute transverse myelitis and a combination of polyradiculitis and anterior horn syndrome. Antiviral treatment and steroids are controversial, and the prognosis of neurological sequelae is largely unknown.

Sepsis calculator implementation reduces empiric antibiotics for suspected early-onset sepsis.

Significant overtreatment with antibiotics for suspected early onset sepsis (EOS) constitutes a persisting clinical problem, generating unnecessary risks, harms, and costs for many newborns. We aimed to study feasibility and impact of a sepsis calculator to help guide antibiotic for suspected EOS in a European setting. In this single-center study, the sepsis calculator was implemented as an addition to and in accordance with existing protocols. One thousand eight hundred seventy-seven newborns ≥ 35 weeks of gestational age were prospectively evaluated; an analogous retrospective control group (n = 2076) was used for impact analysis. We found that empirical treatment with intravenous antibiotics for suspected EOS was reduced from 4.8 to 2.7% after sepsis calculator implementation (relative risk reduction 44% (95% confidence interval 21.4-59.5%)). No evidence for changes in time to treatment start, treatment duration, or proven sepsis rates was found. Adherence to sepsis calculator recommendation was 91%. CONCLUSION: Pragmatic and feasible implementation of the sepsis calculator yields a 44% reduction of empirical use of antibiotics for EOS, without signs of delay or prolongation of treatment. These findings warrant a multicenter, nation-wide, randomized study evaluating systematic use of the sepsis calculator prediction model and its effects in clinical practice outside of the USA. What is known: • Significant overtreatment with antibiotics for suspected early-onset sepsis results in unnecessary costs, risks, and harms. • Implementation of the sepsis calculator in the USA has resulted in a significant decrease in empirical antibiotic treatment, without apparent adverse events. What is new: • Implementation of the sepsis calculator in daily clinical decision-making in a Dutch teaching hospital is feasible in conjunction with existing protocols, with high adherence. • Antibiotic therapy for suspected early-onset sepsis was reduced by 44% following implementation of the calculator.

Prevalence of antimicrobial drug resistant bacteria carried by in- and outpatients attending a secondary care hospital in Zambia.

OBJECTIVE: Antimicrobial resistance is an increasing global health problem. Very little data on resistance patterns of pathogenic bacteria in low-income countries exist. The aim of this study was to measure the prevalence of antimicrobial drug resistant bacteria carried by in- and outpatients in the resource constraint setting of a secondary care hospital in Zambia. Nasal and rectal samples from 50 in- and 50 outpatients were collected. Patients were randomly selected and informed consent was obtained. Nasal samples were tested for the presence of methicillin-resistant Staphylococcus aureus (MRSA), and rectal samples for Gram-negative rods (family of Enterobacteriaceae) non-susceptible to gentamicin, ciprofloxacin and ceftriaxone. Additionally, E-tests were performed on ceftriaxone-resistant Enterobacteriaceae to detect extended-spectrum ß-lactamases (ESBLs). RESULTS: 14% of inpatients carried S. aureus, and 18% of outpatients. No MRSA was found. 90% of inpatients and 48% of outpatients carried one or more Enterobacteriaceae strains (75% Escherichia coli and Klebsiella pneumonia) resistant to gentamicin, ciprofloxacin and/or ceftriaxone (p < 0.001). Among inpatients gentamicin resistance was most prevalent (in 78%), whereas among outpatients ciprofloxacin resistance prevailed (in 38%). All ceftriaxone-resistant Enterobacteriaceae were ESBL-positive; these were present in 52% of inpatients versus 12% of outpatients (p < 0.001). We conclude it is feasible to perform basic microbiological procedures in the hospital laboratory in a low-income country and generate data on antimicrobial susceptibility. The high prevalence of antimicrobial drug resistant Enterobacteriaceae carried by in- and outpatients is worrisome. In order to slow down antimicrobial resistance, surveillance data on local susceptibility patterns of bacteria are a prerequisite to generate guidelines for antimicrobial therapy, to guide in individual patient treatment and to support implementation of infection control measures in a hospital.

Immune status of health care workers to measles virus: evaluation of protective titers in four measles IgG EIAs.

BACKGROUND: Following the recognition of a measles case in a hospital in The Netherlands, health care workers (HCW) from the premises were screened by a commercial enzyme immunoassay (EIA) for measles IgG to identify persons at risk for measles. At least 10% of the HCW were tested measles IgG-negative. As this was considered an unusually high proportion, we hypothesized suboptimal sensitivity of EIAs, especially in medical personnel that had vaccine-induced immunity rather than antibodies resulting from natural infection. OBJECTIVES: To determine (vaccine-induced) measles immunity in HCW, using different EIAs compared to the plaque reduction neutralization (PRN) test, the best surrogate marker for vaccine efficacy and immune protection. STUDY DESIGN: Sera from HCW were tested for measles IgG antibodies in three commercial EIAs, in a bead-based multiplex immunoassay (MIA) and in the PRN test, and evaluated against age and vaccination history of the HCW. RESULTS: Of the 154 HCW, born between 1960 and 1995, 153 (99.4%) had protective levels of measles antibodies (PRN> 120mIU/ml). The three EIAs failed to detect any measles IgG antibodies in approximately 10% of the HCW, while this percentage was approximately 3% for the MIA. Negative IgG results rose to 19% for individuals born between 1975 and 1985, pointing to an age group largely representing vaccinated persons from the first measles vaccination period in The Netherlands. CONCLUSION: The results show limitations in the usefulness of current EIA assays for determining protective measles antibodies in persons with a vaccination history.

Predictive value of prior colonization and antibiotic use for third-generation cephalosporin-resistant enterobacteriaceae bacteremia in patients with sepsis.

BACKGROUND: To prevent inappropriate empiric antibiotic treatment in patients with bacteremia caused by third-generation cephalosporin (3GC)-resistant Enterobacteriaceae (3GC-R EB), Dutch guidelines recommend ß-lactam and aminoglycoside combination therapy or carbapenem monotherapy in patients with prior 3GC-R EB colonization and/or recent cephalosporin or fluoroquinolone usage. Positive predictive values (PPVs) of these determinants are unknown. METHODS: We retrospectively studied patients with a clinical infection in whom blood cultures were obtained and empiric therapy with broad-spectrum ß-lactams and/or aminoglycosides and/or fluoroquinolones was started. We determined the PPVs of prior colonization and antibiotic use for 3GC-R EB bacteremia, and the consequences of guideline adherence on appropriateness of empiric treatment. RESULTS: Of 9422 episodes, 773 (8.2%) were EB bacteremias and 64 (0.7%) were caused by 3GC-R EB. For bacteremia caused by 3GC-R EB, PPVs of prior colonization with 3GC-R EB (90-day window) and prior usage of cephalosporins or fluoroquinolones (30-day window) were 7.4% and 1.3%, respectively, and PPV was 1.8% for the presence of any of these predictors. Adherence to Dutch sepsis guideline recommendations was 27%. Of bacteremia episodes caused by 3GC-R and 3GC-sensitive EB, 56% and 94%, respectively, were initially treated with appropriate antibiotics. Full adherence to guideline recommendations would hardly augment proportions of appropriate therapy, but could considerably increase carbapenem use. CONCLUSIONS: In patients receiving empiric treatment for sepsis, prior colonization with 3GC-R EB and prior antibiotic use have low PPV for infections caused by 3GC-R EB. Strict guideline adherence would unnecessarily stimulate broad-spectrum antibiotic use.

Appropriateness of empirical treatment and outcome in bacteremia caused by extended-spectrum-ß-lactamase-producing bacteria.

We studied clinical characteristics, appropriateness of initial antibiotic treatment, and other factors associated with day 30 mortality in patients with bacteremia caused by extended-spectrum-ß-lactamase (ESBL)-producing bacteria in eight Dutch hospitals. Retrospectively, information was collected from 232 consecutive patients with ESBL bacteremia (due to Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae) between 2008 and 2010. In this cohort (median age of 65 years; 24 patients were <18 years of age), many had comorbidities, such as malignancy (34%) or recurrent urinary tract infection (UTI) (15%). One hundred forty episodes (60%) were nosocomial, 54 (23%) were otherwise health care associated, and 38 (16%) were community acquired. The most frequent sources of infection were UTI (42%) and intra-abdominal infection (28%). Appropriate therapy within 24 h after bacteremia onset was prescribed to 37% of all patients and to 54% of known ESBL carriers. The day 30 mortality rate was 20%. In a multivariable analysis, a Charlson comorbidity index of ≥ 3, an age of ≥ 75 years, intensive care unit (ICU) stay at bacteremia onset, a non-UTI bacteremia source, and presentation with severe sepsis, but not inappropriate therapy within <24 h (adjusted odds ratio [OR], 1.53; 95% confidence interval [CI], 0.68 to 3.45), were associated with day 30 mortality. Further assessment of confounding and a stratified analysis for patients with UTI and non-UTI origins of infection did not reveal a statistically significant effect of inappropriate therapy on day 30 mortality, and these results were insensitive to the possible misclassification of patients who had received ß-lactam-ß-lactamase inhibitor combinations or ceftazidime as initial treatment. In conclusion, ESBL bacteremia occurs mostly in patients with comorbidities requiring frequent hospitalization, and 84% of episodes were health care associated. Factors other than inappropriate therapy within <24 h determined day 30 mortality.

[Fever, malaise and eosinophilia after consumption of raw fish in Italy: infection by a liver fluke (Opisthorchis felineus)]. / Koorts, malaise en eosinofilie na eten van rauwe vis in Italië: infectie met leverbot (Opisthorchis felineus).

BACKGROUND: Infection by a liver fluke (trematode) is rare in Western Europe, but recently a few outbreaks caused by this parasite have been described after consumption of raw freshwater fish caught in Italy. CASE DESCRIPTION: A 35-year-old Dutch woman presented with fever, without localising symptoms. Laboratory tests showed pronounced eosinophilia. Microscopy of the faeces showed a liver fluke egg. Upon inquiry, it appeared that she had consumed raw fish (carpaccio of tench) three weeks earlier in a restaurant in Northern Italy. In Italy, 45 people with comparable symptoms were found to be infected by the same parasite. All patients had eaten in the same restaurant. They were treated successfully with praziquantel. The stool egg was from the trematode Opisthorchis felineus. CONCLUSION: O. felineus lives in the bile ducts of fish-eating mammals. Its life cycle includes freshwater snails and fish. Acute symptoms are fever, malaise and abdominal pain and complications such as liver and bile duct abscesses and cholangitis. Diagnosis is made by microscopic examination of the faeces, confirmed by PCR or by serology.

A prospective, community-based study on virologic assessment among elderly people with and without symptoms of acute respiratory infection.

BACKGROUND/OBJECTIVES: Community-based elderly studies concerning microbiology of acute respiratory infections are scarce. Data on subclinical infections are even totally absent, although asymptomatic persons might act as a source of respiratory infections. METHODS: In a 1-year community-based study, we prospectively investigated the possible virologic cause of acute respiratory infections in 107 symptomatic case episodes and 91 symptom-free control periods. Participants, persons >/=60 years, reported daily the presence of respiratory symptoms in a diary. Virologic assessment was performed by polymerase chain reaction (PCR) and serology. RESULTS: In 58% of the case episodes a pathogen was demonstrated, the most common being rhinoviruses (32%), coronaviruses (17%), and influenzaviruses (7%). The odds ratio for demonstrating a virus in cases with symptoms vs. controls without symptoms was 30.0 (95% confidence interval 10.2-87.6). In 4% of the symptom-free control periods a virus was detected. CONCLUSIONS: This study supports the importance of rhinovirus infections in community-dwelling elderly persons, whereas asymptomatic elderly persons can also harbor pathogens as detected by PCR, and thus might be a source of infection for their environment.

Demonstration by a nested PCR for Mycoplasma pneumoniae that M. pneumoniae load in the throat is higher in patients hospitalised for M. pneumoniae infection than in non-hospitalised subjects.

A nested PCR protocol to detect Mycoplasma pneumoniae DNA in throat specimens was developed. An amplification control (AC) template, which is amplified by the same primers as the M. pneumoniae target sequence, was constructed. The assay allowed highly specific and sensitive detection of M. pneumoniae DNA. In all, 305 throat samples, 62 from hospitalised patients and 243 from non-hospitalised subjects, were analysed by the nested PCR. Inhibition of the PCR was observed in 20% of the samples, but was abolished after a 1 in 10 dilution. Throat samples from 5 (8%) of the hospitalised patients and from 7 (3%) of the non-hospitalised subjects were positive for M. pneumoniae DNA. To investigate the relationship between M. pneumoniae load and the severity of disease, the M. pneumoniae load in 10 throat samples from M. pneumoniae-positive subjects was assessed semi-quantitatively by application of the nested PCR to a series of limiting dilutions of nucleic acid extracted from these throat samples. The calculated M. pneumoniae load varied from 20 to 3830 cfu/ml of throat sample. The mean M. pneumoniae load in samples from the hospitalised patients was significantly higher than that in samples from the non-hospitalised subjects. The nested PCR is a useful tool to detect M. pneumoniae DNA in the throat and to study the relationship between the load of M. pneumoniae in throat samples and severity of disease due to M. pneumoniae infection.