Development of a decision support tool to compare diagnostic strategies for establishing the herd status for infectious diseases: An example with Salmonella Dublin infection in dairies.

The diagnosis of infectious diseases at herd level can be challenging as different stakeholders can have conflicting priorities. The current study proposes a "proof of concept" of an approach that considers a reasonable number of criteria to rank plausible diagnostic strategies using multi-criteria decision analysis (MCDA) methods. The example of Salmonella Dublin diagnostic in Québec dairy herds is presented according to two epidemiological contexts: (i) in herds with no history of S. Dublin infection and absence of clinical signs, (ii) in herds with a previous history of infection, but absence of clinical signs at the moment of testing. Multiple multiparty exchanges were conducted to determine: 1) stakeholders' groups; 2) the decision problem; 3) solutions to the problem (options) or diagnostic strategies to be ordered; 4) criteria and indicators; 5) criteria weights; 6) the construction of a performance matrix for each option; 7) the multi-criteria analyses using the visual preference ranking organization method for enrichment of evaluations approach; 8) the sensitivity analyses, and 9) the final decision. A total of nine people from four Québec's organizations (the dairy producers provincial association along with the DHI company, the ministry of agriculture, the association of veterinary practitioners, and experts in epidemiology) composed the MCDA team. The decision problem was "What is the optimal diagnostic strategy for establishing the status of a dairy herd for S. Dublin infection when there are no clinical signs of infection?". Fourteen diagnostic strategies composed of the three following parameters were considered: 1) biological samples (bulk tank milk or blood from 10 heifers aged over three months); 2) sampling frequencies (one to three samples collection visits); 3) case definitions to conclude to a positive status using imperfect milk- or blood-ELISA tests. The top-ranking diagnostic strategy was the same in the two contexts: testing the bulk tank milk and the blood samples, all samples collected during one visit and the herd being assigned a S. Dublin positive status if one sample is ELISA-positive. The final decision favored the top-ranking option for both contexts. This MCDA approach and its application to S. Dublin infection in dairy herds allowed a consensual, rational, and transparent ranking of feasible diagnostic strategies while taking into account the diagnostic tests accuracy, socio-economic, logistic, and perception considerations of the key actors in the dairy industry. This promising tool can be applied to other infectious diseases that lack a well-established diagnostic procedure to define a herd status.

Accuracy of testing strategies using antibody-ELISA tests on repeated bulk tank milk samples and/or sera of individual animals for predicting herd status for Salmonella dublin in dairy cattle.

There is currently no perfect test for determining herd-level status for Salmonella Dublin in dairy cattle herds. Our objectives were to evaluate the accuracy, predictive ability, and misclassification cost term of different testing scenarios using repeated measurements for establishing the S. Dublin herd status. Diagnostic strategies investigated used repeated bulk tank milk antibody-ELISA tests, repeated rounds of blood antibody-ELISA tests on non-lactating animals or a combination of both approaches. Two populations hypothesized to have different S. Dublin prevalences were included: (i) a convenience sample of 302 herds with unknown history of infection; and (ii) a cohort of 58 herds that previously tested positive to S. Dublin. Bulk milk samples were collected monthly for 6-7 months and serum were obtained from 10 young animals on two occasions, at the beginning and end of bulk milk sampling period. A series of Bayesian latent class models for two populations and comparing two tests were used to compare bulk milk-based to serum-based strategies. Moreover, Monte Carlo simulations were used to compared diagnostic strategies combining both types of samples. For each diagnostic strategy, we estimated the predictive values using two theoretical prevalences (0.05 and 0.25). Misclassification cost term was also estimated for each strategy using these two prevalences and a few relevant false-negative to false-positive cost ratios. When used for screening a population with an expected low prevalence of disease, for instance for screening herds with no clinical signs and no previous S. Dublin history, a diagnostic strategy consisting of two visits at 6 months interval, and with herd considered positive if bulk milk PP% ≥ 35 and/or ≥ 1/10 animals are positive on one or both visits could be used to confidently rule-out S. Dublin infection (median negative predictive value of 0.99; 95% Bayesian credible intervals, 95BCI: 0.98, 1.0). With this approach, however, positive results should later be confirmed with more specific tests to confirm whether S. Dublin is truly present (median positive predictive value of 0.36; 95BCI: 0.22, 0.57). The same diagnostic strategy could also be used confidently to reassess the S. Dublin status in herds with a previous S. Dublin history. When use for such a purpose, the predictive value of a positive result could be greatly improved, from 0.78 (95BCI: 0.65, 0.90) to 0.99 (95BCI: 0.94, 1.0) by requiring ≥ 1 positive result on both visits, rather than at any of the two visits.

Risk of Neutropenia in Adults Treated with Piperacillin-Tazobactam or Cefazolin: A Retrospective Cohort Study.

Background: Neutropenia is an adverse effect associated with the use of several antibiotics, including piperacillin-tazobactam (P/T). Previous findings have suggested that the risk of neutropenia in children is significantly higher with P/T than with ticarcillin-clavulanate. Objectives: To compare the risk of neutropenia associated with P/T and with cefazolin in an adult population and to describe the characteristics of neutropenia episodes observed. Methods: This descriptive retrospective study involved patients aged 18 years or older who received a minimum of 10 days of treatment with P/T or cefazolin between January 2009 and December 2013. Patients who experienced neutropenia (absolute neutrophil count < 1.5 × 109/L) were compared, using univariate and multivariate logistic regression models, between those who received P/T and those who received cefazolin. Results: A total of 207 patients were included (104 who received P/T and 103 who received cefazolin). Ten episodes of neutropenia were observed, 5 with each antibiotic (4.8% and 4.9%, respectively; odds ratio 0.99, 95% confidence interval 0.278-3.527). The mean cumulative dose of piperacillin was 290.4 g among patients who experienced neutropenia and 247.0 g among all patients treated with P/T, and the mean treatment duration was 24.0 days and 21.0 days, respectively. The average time before the onset of neutropenia was slightly longer with P/T than with cefazolin (22.0 versus 17.2 days, p = 0.38). Conclusions: Although these results require confirmation in a larger clinical trial (to lessen possible attribution bias), the risk of neutropenia appeared to be similar between P/T and cefazolin.

Contexte: La neutropénie est un effet indésirable associé à l'utilisation de plusieurs antibiotiques, dont la pipéracilline-tazobactam (P/T). Des données récentes indiquent que le risque de neutropénie chez les enfants est significativement plus élevé avec la P/T qu'avec l'association ticarcilline-clavulanate. Objectifs: Comparer le risque de neutropénie associé à la P/T et à la céfazoline chez une population adulte et décrire les caractéristiques des épisodes de neutropénie observés. Méthodes: Cette étude rétrospective descriptive impliquait des patients âgés d'au moins 18 ans ayant reçu un traitement d'au moins 10 jours par P/T ou céfazoline entre janvier 2009 et décembre 2013. Les patients ayant présenté une neutropénie (nombre absolu de neutrophiles < 1,5 × 109/L) ont été comparés, à l'aide de modèles de régression logistique univariée et multivariée, entre ceux qui ont reçu de la P/T et ceux qui ont reçu de la céfazoline. Résultats: Au total, 207 patients ont été inclus (104 ayant reçu de la P/T et 103 ayant reçu de la céfazoline). Dix épisodes de neutropénie ont été observés, 5 avec chaque antibiotique (4,8 % et 4,9 %, respectivement; rapport des cotes 0,99; intervalle de confiance à 95 % 0,278­3,527). La dose cumulée moyenne de pipéracilline était de 290,4 g chez les patients ayant présenté une neutropénie et de 247,0 g chez tous les patients traités par P/T. La durée moyenne du traitement était de 24,0 jours et 21,0 jours, respectivement. Le délai moyen avant l'apparition de la neutropénie était légèrement plus long avec la P/T qu'avec la céfazoline (22,0 contre 17,2 jours, p = 0,38). Conclusions: Bien que ces résultats nécessitent une confirmation dans un essai clinique de plus grande envergure (afin de réduire d'éventuels biais d'attribution), le risque de neutropénie semble être similaire chez les personnes ayant reçu de la P/T et ceux ayant reçu de la céfazoline.

Estimation of the accuracy of an ELISA test applied to bulk tank milk for predicting herd-level status for Salmonella Dublin in dairy herds using Bayesian Latent Class Models.

Enzyme-Linked Immunosorbent Assay (ELISA) test is commonly used for detection of antibodies to Salmonella Dublin in individual bovine milk samples. However, little is known about its accuracy when used on bulk tank milk for determining herd-level S. Dublin status and when evaluated without assuming a perfect reference test. The objectives of this study were: i) to estimate the herd prevalence of S. Dublin among dairy cattle herds in Québec, Canada; ii) to estimate the herd sensitivity and specificity of a commercially available ELISA test when used on bulk milk; iii) to examine how the diagnostic test accuracy varies with different bulk milk ELISA cut-offs; and (iv) to assess the added value of combining ELISA screening of bulk milk and individual serum of 10 animals for determining S. Dublin herd status. A cohort of 302 dairy herds selected in three regions (population 1) and 58 herds that have already tested positive to S. Dublin (population 2) were recruited. A total of 715 bulk milk samples and 7150 individual blood samples from cattle over 3 months old (10 animals per herd) sampled on two occasions were collected. Testing was conducted using PrioCHECK™ Salmonella Ab bovine Dublin ELISA test for milk (Bmilk ELISA: test under investigation) and for serum of 10 individual animals (Serum10 ELISA: imperfect reference test) to determine the herd-level S. Dublin status. A latent class model for two populations, two tests, allowing for conditional dependence between tests was fit within a Bayesian framework. At cut-off PP % ≥ 15 for a Bmilk ELISA, which is used by provincial authorities, the herd prevalence of S. Dublin estimated using informative prior was 6.8 % (4.3-9.9) in population 1. The herd sensitivity and specificity estimates (95 % Bayesian Credibility Intervals) for Bmilk ELISA were 40.6 % (15.6-88.8) and 91.9 % (88.3-95.8), respectively. Positive and negative predictive values of Bmilk ELISA applied in population 1 were 26.4 % (8.5-60.2) and 95.8 % (92.1-99.2), respectively. Increasing Bmilk ELISA cut-offs had little influence on predictive values. The combination of both ELISA tests did not improve the diagnostic accuracy of S. Dublin. Our study shows that a test-positive herd based on a single bulk milk sample would require complementary tests for status confirmation. However, a test-negative herd could be classified as true negative with a high certainty.

Role of high-risk antibiotic use in incidence of health-care-associated Clostridioides difficile infection in Quebec, Canada: a population-level ecological study.

BACKGROUND: The incidence of health-care-associated Clostridioides difficile infections has been declining in the Canadian province of Quebec since 2015. We examined whether changes in high-risk antibiotic use could account for this decrease, as reported in other jurisdictions. METHODS: We did a retrospective interrupted time-series analysis of 12 hospitals in the Canadian province of Quebec, representing a quarter of all health-care-associated C difficile infections in this region between April 1, 2012, and March 31, 2017. Data for high-risk antibiotic use (eg, amoxicillin-clavulanate, cephalosporins, fluoroquinolones, and clindamycin) in defined daily doses (DDDs) were extracted from local surveillance databases, and incidences of health-care-associated C difficile infections were extracted from provincial surveillance databases. We used hierarchical segmented Poisson regression to assess whether variations in rates of health-care-associated C difficile infections followed variations in antibiotic use. FINDINGS: Overall, 4455 health-care-associated C difficile infections and 6 281 960 patient-days were reported in the 12 participating hospitals, representing around a quarter of the provincial data. A 50% decrease in the annual incidence of health-care-associated C difficile infections was recorded between 2012-13 and 2016-17 (9·4 infections per 10 000 patient-days vs 4·7 infections per 10 000 patient-days), and a 67% decrease in the proportion of these infections due to the NAP1/027 strain of C difficile was seen (64% in 2013 vs 21% in 2017). In total, 1 266 960 DDDs of high-risk antibiotics were distributed during the study period. An increasing time trend was noted in high-risk antibiotic use, reaching a total of 223 DDDs per 1000 patient-days in 2016-17. An increase of one DDD per 1000 patient-days was associated with a 0·2% increase in the rate of health-care-associated C difficile infections in the following 4-week period. A significant change in incidence of health-care-associated C difficile infections persisted despite adjustment for high-risk antibiotic use, as shown by a significant residual step change (0·825, 95% CI 0·731-0·932) and change in trend (0·987, 0·980-0·994). INTERPRETATION: Changes in use of high-risk antibiotics do not entirely account for the sudden decrease in health-care-associated C difficile infections in the Canadian province of Quebec since 2015. Further studies are needed to understand factors implicated in the change in epidemiology of health-care-associated C difficile infections. FUNDING: Institut National de Santé Publique du Québec.

Higher risk of neutropenia associated with piperacillin-tazobactam compared with ticarcillin-clavulanate in children.

BACKGROUND: A series of cases of piperacillin-tazobactam (P/T)-associated neutropenia has been observed recently in children in our center. Because neutropenia was seldom observed in children treated with ticarcillin-clavulanic acid (T/C), we conducted a study to determine if there is an increased risk of neutropenia in children exposed to P/T in comparison with T/C. METHODS: Medical records of subjects aged <18 years who received at least 1 dose of P/T or T/C between 1 January 2008 and 30 June 2011 were reviewed. RESULTS: Two hundred ninety-nine episodes of treatment (65 P/T, 234 T/C) met inclusion criteria. Among those episodes, 213 had data allowing complete white blood cell count analysis and were included in the final analysis. Thirteen cases of neutropenia were observed during the study period. The average time to onset was 17.6 days and all patients were aged <13 years. Seven cases (10.8%) occurred in the P/T group and 6 (2.6%) in the T/C group (unadjusted odds ratio, 4.59; 95% confidence interval, 1.48-14.17). Although a statistically significant correlation was observed between age, treatment duration, and total dose and the development of neutropenia (r = -0.121, P = .037; r = 0.267, P < .001; r = 0.260, P < .001, respectively), this was not the case for sex, indications, neutrophil count at initiation, and concomitant drug treatments. CONCLUSIONS: Although our results need to be confirmed, they suggest that children receiving long courses of therapy (>2 weeks) with P/T may be at increased risk of neutropenia, compared with T/C.

Prevalence of contagious mastitis pathogens in bulk tank milk in Québec.

The objective of this study was to estimate the prevalence of mycoplasma, Staphylococcus aureus, and Streptococcus agalactiae in bulk tank milk (BTM) in Québec dairy herds. BTM was sampled 3 times a month in 117 randomly selected dairy herds. Samples were submitted for S. aureus, S. agalactiae, and mycoplasma and for direct mycoplasma detection by polymerase chain reaction (PCR). Mycoplasma spp. was identified at least once in 3 herds (2.6%) by primary culture and/or PCR and in 4 herds (3.4%) by enrichment culture and/or PCR. Staphylococcus aureus was isolated at least once in 99 (84.6%) and 112 (95.7%) herds in primary culture and after enrichment, respectively. Streptococcus agalactiae was isolated at least once in 9 (7.7%) and 10 (8.6%) herds in primary culture and after enrichment, respectively. Herd prevalence of mycoplasma was similar to that previously reported in Canada. Staphylococcus aureus is still by far the most important contagious mastitis pathogen.

Prévalence dans le lait de réservoir des agents pathogènes responsables de mammites contagieuses au Québec. L'objectif de cette étude était d'évaluer la prévelance de mycoplasmes, Stapylococcus aureus et Streptococcus agalactiae dans le lait de réservoir des troupeaux laitiers québécois. Dans 117 troupeaux sélectionnés aléatoirement, le lait de réservoir a été prélevé une fois par mois 3 mois de suite. Les prélèvements ont été soumis pour la recherche par culture de S. aureus, S. agalactiae et mycoplasmes ainsi que pour recherche directe par PCR pour mycoplasmes. Mycoplasma spp. a été identifié au moins une fois dans 3 troupeaux (2,6 %) en culture primaire ou PCR et dans 4 troupeaux (3,4 %) par enrichissement ou PCR. Staphylococcus aureus a été isolé au moins une fois dans 99 (84,6 %) et 112 (95,7 %) troupeaux en culture primaire et après enrichissement, respectivement. Streptococcus agalactiae a été isolé au moins une fois dans 9 (7,7 %) et 10 (8,6 %) troupeaux en culture primaire et après enrichissement, respectivement. La prévalence de troupeau de mycoplasmes est similaire à celle rapportée précédemment au Canada. Staphylococcus aureus est de loin le plus fréquent pathogène de mammite contagieuse.(Traduit par les auteurs).

Clostridium difficile-associated diarrhoea rates and global antibiotic consumption in five Quebec institutions from 2001 to 2004.

A massive outbreak of a new Clostridium difficile clone affected the province of Quebec between 2002 and 2004. There are several theories as to the exact cause of the emergence of this new clone, including the overuse of some classes of antibiotics. Antibiotic prescription is associated with C. difficile-associated diarrhoea (CDAD), but which class has the highest risk is still the subject of debate. We analysed the global antibiotic consumption patterns in five institutions in Quebec, three in the area affected by the 2002-2004 CDAD outbreak and two in non-affected areas. We showed that there is no correlation between the type and amount of antibiotics used at the institution level and the magnitude of the outbreak. Deficient infection control measures likely led to the rapid spread and dissemination of this newly characterised clone within some parts of Quebec.

Serotonin toxicity associated with concomitant use of linezolid.

OBJECTIVE: To report 2 cases of serotonin toxicity (ST) associated with concomitant use of linezolid and serotonergic drugs and review previously published case reports. CASE SUMMARIES: Case 1. A 38-year-old white female with cystic fibrosis treated with venlafaxine 300 mg/day for one year was prescribed linezolid 600 mg intravenously every 12 hours for treatment of methicillin-resistant Staphylococcus aureus (MRSA) pulmonary infection. She displayed symptoms of ST 8 days after the introduction of linezolid. The venlafaxine dosage was decreased to 150 mg/day, and symptoms gradually abated over 36 hours. Case 2. A 37-year-old male with multiple myeloma received citalopram 40 mg/day and trazodone 150 mg/day for anxiety-related disorders. Linezolid treatment with 600 mg orally twice daily was instituted for MRSA cellulitis. The following day, the patient developed anxiety, panic attacks, tremors, tachycardia, and hypertension that persisted throughout linezolid treatment. Symptoms finally waned 5 days after linezolid treatment was stopped. DISCUSSION: The symptoms observed in our patients were consistent with Sternbach's criteria for ST. A review of published case reports showed a short time to onset of symptoms following the introduction of linezolid, generally within 1-3 days. Also of note is the use of relatively high dosages of serotonergic drugs. Use of the Naranjo probability scale indicated a possible relationship between the use of linezolid and the occurrence of ST in both cases. CONCLUSIONS: Clinicians should pay special attention to patients treated with serotonergic drugs, especially those receiving dosages in the higher end of the normal range who are prescribed linezolid, and consider tapering or reducing the dosage of serotonergic drugs for the duration of antibiotic therapy.