Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis: A Prospective Multicenter Study.

BACKGROUND: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).

Workload, diagnostic work-up and treatment of urinary tract infections in adults during out-of-hours primary care: a retrospective cohort study.

BACKGROUND: Urinary tract infections (UTIs) are one of the most common infections in primary care. Previous research showed that GPs find it challenging to diagnose UTIs and frequently divert from guidelines leading to unwarranted antibiotic prescriptions and inefficient use of diagnostics such as urinary cultures. We hypothesise that management of UTIs during out-of-hours care may be extra challenging due to a higher workload and logistical issues regarding diagnostic work-up and obtaining results. We therefore aimed to study the workload, diagnostic work-up and treatment of UTIs during out-of-hours primary care. METHODS: We performed a retrospective observational cohort study in which we analysed a full year (2018) of electronic patient records of two large Dutch GP out-of-hours centres. All adult patients with UTI symptoms were included in this study. Descriptive statistics and multivariate regression were used to analyse diagnostics and subsequent management. RESULTS: A total of 5657 patients were included (78.9% female, mean age of 54 years), with an average of eight patients per day that contact a GP out-of-hours centre because of UTI symptoms. Urinary dipsticks were used in 87.5% of all patients visiting the out-of-hours centres with UTI symptoms. Strikingly, urinary cultures were only requested in 10.3% of patients in which urinary culture was indicated. Seventy-four percent of the patients received antibiotics. Seventy-nine percent of the patients with a negative nitrite test still received antibiotics. Remarkably, patients at risk of complications because of a UTI, such as men, received fewer antibiotic prescriptions. CONCLUSIONS: In total, 74% of the patients received antibiotics. 8 out of 10 patients still received an antibiotic prescription in case of a negative nitrite test, and 9 out of 10 patients with an indication did not receive a urine culture. In conclusion, we found that correctly diagnosing UTIs and prescribing antibiotics for UTIs is a challenge that needs major improvement, especially during out-of-hours GP care.

The diagnosis and treatment of invasive aspergillosis in Dutch haematology units facing a rapidly increasing prevalence of azole-resistance. A nationwide survey and rationale for the DB-MSG 002 study protocol.

Patients with haematological malignancies are at risk for invasive fungal diseases (IFD). A survey was conducted in all Dutch academic haematology centres on their current diagnostic, prophylactic and therapeutic approach towards IFD in the context of azole-resistance. In all 8 centres, a haematologist and microbiologist filled in the questionnaire that focused on different subgroups of haematology patients. Fungal prophylaxis during neutropaenia was directed against Candida and consisted of fluconazole and/or amphotericin B suspension. Mould-active prophylaxis was given to acute myeloid leukaemia patients during chemotherapy in 2 of 8 centres. All centres used azole prophylaxis in a subset of patients with graft-versus-host disease. A uniform approach towards the diagnosis and treatment of IFD and in particular azole-resistant Aspergillus fumigatus was lacking. In 2017, all centres agreed to implement a uniform diagnostic and treatment algorithm regarding invasive aspergillosis with a central role for comprehensive diagnostics and PCR-based detection of azole-resistance. This study (DB-MSG 002) will re-evaluate this algorithm when 280 patients have been treated. A heterogeneous approach towards antifungal prophylaxis, diagnosis and treatment was apparent in the Netherlands. Facing triazole-resistance, consensus was reached on the implementation of a uniform diagnostic approach in all 8 centres.

Alternative diagnosis in the putative ventilator-associated pneumonia patient not meeting lavage-based diagnostic criteria.

BACKGROUND: The clinical picture of ventilator-associated pneumonia (VAP) can be mimicked by other infectious and non-infectious diseases. The aim of this study was to determine the alternative diagnoses and to develop a diagnostic flow chart for patients suspected of having VAP not meeting the diagnostic broncho-alveolar lavage (BAL) criteria. METHODS: Adult intensive care patients with a clinical suspicion of VAP and negative BAL results were included. The clinical suspicion of VAP was based on the combination of clinical, radiological, and microbiological criteria. BAL was considered positive if cell differentiation revealed ≥ 2% cells with intracellular organisms and/or quantitative culture results of ≥ 10(4) cfu/ml. The most likely alternative diagnosis of fever and pulmonary densities was retrospectively determined by two authors independently. RESULTS: In all, 110 of 207 patients with suspected VAP did not meet the diagnostic BAL criteria and required further diagnostic evaluation. In 67 patients an alternative diagnosis for fever could be found. In 51 patients an alternative diagnosis of both fever and pulmonary densities could be established. In almost 40% of patients no alternative diagnosis could be provided. Non-bacterial pneumonia was diagnosed in 10 patients with Herpes simplex virus 1 (HSV-1) as the most common pathogen. In eight patients non-infectious pneumonitis was diagnosed. CONCLUSION: Due to the wide range of alternative diagnoses and applied tests the diagnostic work-up proved to be necessarily individualized and guided by repeated clinical assessment. The most frequently found alternative diagnoses were viral pneumonia and non-infectious pneumonitis.

Physician-Targeted Interventions in Antibiotic Prescribing for Urinary Tract Infections in General Practice: A Systematic Review.

Urinary tract infections (UTIs) are the most common reason for women to consult a general practitioner (GP). While UTIs are self-limiting in half of cases, most women are prescribed antibiotics, often in discordance with established guidelines. Researchers have employed different interventions to improve GPs' prescribing behavior, especially for respiratory infections, but it is uncertain whether these are effective for UTI care. Therefore, we performed a systematic review, including (cluster) randomized clinical trials investigating the effect of interventions targeted at GPs to improve antibiotic prescriptions for UTI. From September to December 2021 we searched the Medline, Web of Science, and CENTRAL databases, ultimately including ten studies describing eleven trials. We determined the effect of the interventions on the decision to prescribe and on the choice of antibiotic. Results showed that most studies employed multifaceted interventions, most frequently including audit & feedback and/or educational meetings. Seven out of nine trials that recorded first-choice prescriptions saw an increased proportion of first-choice antibiotics in the intervention groups compared to control groups. The employed interventions also caused a decreased proportion of at least one broad-spectrum antibiotic in five out of six studies that measured broad-spectrum antibiotic prescriptions. However, the total number of antibiotic prescriptions for UTIs increased in four out of eight studies. Therefore, while effective at influencing GPs' prescribing behavior, future interventions should also focus on improving the decision to prescribe at all.

Cross-sectional internet survey exploring women's knowledge, attitudes and practice regarding urinary tract infection-related symptoms in the Netherlands.

OBJECTIVES: Urinary tract infections (UTIs) are the most prevalent cause for women to consult a general practitioner (GP) and are commonly treated with (broad-spectrum) empirical antibiotics, even though 50% of UTIs are self-limiting. In this study, we aim to explore women's attitudes and experiences regarding UTIs, in order to determine patients' willingness to accept delayed antibiotic prescriptions. DESIGN: An internet-based cross-sectional survey SETTING: We recruited participants during 2 weeks of March and April in 2020 through several social media platforms. PARTICIPANTS: We obtained 1476 responses, of which 975 were eligible for analysis. RESULTS: We asked women about their knowledge, attitudes and practice regarding UTI-related symptoms. Participants ranked 'confirmation of diagnosis' (43.8%) as the most important reason to consult a GP with urinary symptoms, followed by 'pain relief' (32%), and 'antibiotic prescription' (14.3%). For treatment, 71% of participants reported that their GP prescribed immediate antibiotics, while only 3% received a delayed antibiotic prescription and 1% was advised pain medication. Furthermore, 50% of respondents were aware of the possible self-limiting course of UTIs and 70% would be willing to accept delayed antibiotic treatment, even if a certain diagnosis of UTI was established. Willingness to delay was lower in experienced patients compared to inexperienced patients. CONCLUSIONS: Women are quite receptive to delayed antibiotics as an alternative to immediate antibiotics for UTIs or urinary symptoms. GPs should consider discussing delayed antibiotic treatment more often with women presenting with urinary symptoms.

Probiotics for prevention of nosocomial infections: efficacy and adverse effects.

PURPOSE OF REVIEW: In this era of increasing antimicrobial resistance, use of probiotics in infection prevention has brought new perspective. However, in 2008 the, until then considered, safe use of probiotics became an important topic after publication of a trial showing excess mortality in patients on probiotic prophylaxis. In this article, we review the concept of infection prevention by probiotics and the present knowledge of the efficacy of probiotics in prevention of infections among patients with abdominal diseases and in intensive care. Safety issues of probiotics will be discussed extensively. RECENT FINDINGS: Over 30 clinical trials with probiotics to prevent infections have been published, some of which were prematurely stopped recently. Studies with critically ill patients and patients with abdominal diseases showed conflicting results regarding the effects of probiotics on infection rates, as did meta-analyses. These studies are difficult to compare because different probiotics were used which all have different efficacy and safety profiles. SUMMARY: The efficacy of probiotics in infection prevention among critically ill patients is still not unequivocally determined. The safety profile differs per probiotic strain and should not be generalized towards other strains and patient populations. A well designed and well powered clinical trial with clear endpoints to demonstrate efficacy is warranted.

Treating (Recurrent) Vulvovaginal Candidiasis with Medical-Grade Honey-Concepts and Practical Considerations.

Recurrent vulvovaginal candidiasis (RVVC) is a relapsing vaginal fungal infection caused by Candida species. The prevalence varies among age populations and can be as high as 9%. Treatment options are limited, and in 57% of the cases, relapses occur within six months after fluconazole maintenance therapy, which is the current standard of care. The pathogenesis of RVVC is multifactorial, and recent studies have demonstrated that the vaginal microenvironment and activity of the immune system have a strong influence on the disease. Medical-grade honey (MGH) has protective, antimicrobial, and immunomodulatory activity and forms a putative alternative treatment. Clinical trials have demonstrated that honey can benefit the treatment of bacterial and Candida-mediated vaginal infections. We postulate that MGH will actively fight ongoing infections; eradicate biofilms; and modulate the vaginal microenvironment by its anti-inflammatory, antioxidative, and immunomodulatory properties, and subsequently may decrease the number of relapses when compared to fluconazole. The MGH formulation L-Mesitran Soft has stronger antimicrobial activity against various Candida species than its raw honey. In advance of a planned randomized controlled clinical trial, we present the setup of a study comparing L-Mesitran Soft with fluconazole and its practical considerations.

Appropriateness of empirical antibiotic therapy and added value of adjunctive gentamicin in patients with septic shock: a prospective cohort study in the ICU.

OBJECTIVES: To determine the appropriateness of empiric antibiotic therapy and the possible benefit of adding short-course gentamicin in septic shock patients with abdominal, urogenital, or an unknown focus. Secondary objectives were the effect of gentamicin addition on shock reversal and the incidence of a fungal infection. METHODS: Microbiological cultures, antibiotic treatment, and antibiotic resistance patterns of the cultured microorganisms were recorded during the first 5 days of admission. Inappropriate antibiotic therapy was defined as a prescription within the first 24 h that did not cover cultured bacteria during the first 5 days of admission and was determined in the overall group and in patients receiving adjunctive gentamicin (combination therapy) versus patients receiving monotherapy. Binomial logistic regression analysis was used to investigate the association of gentamicin addition with shock reversal. RESULTS: Of 203 septic shock patients, with abdominal (n = 143), urogenital (n = 27) or unknown (n = 33) focus, 115 patients received monotherapy, and 88 patients received combination therapy. Inappropriate therapy occurred in 29 patients (14%), more frequently in monotherapy (17%) versus combination therapy (10%). Combination therapy would have been effective in 55% of patients with inappropriate monotherapy. We found no association between gentamicin addition and shock reversal (p = .223). A fungal infection was present in 22 patients (11%). CONCLUSION: Inappropriate empirical antibiotic therapy occurs in 17% of septic shock patients receiving monotherapy. In 55% of these patients, additional gentamicin would have resulted in appropriate therapy. When clinical course is unfavourable, lowering the threshold for administering adjunctive aminoglycoside and antifungal therapy should be considered.

Probiotics versus antibiotic decontamination of the digestive tract: infection and mortality.

PURPOSE: Selective decontamination of the digestive tract (SDD) has been shown to decrease the infection rate and mortality in intensive care units (ICUs); Lactobacillus plantarum 299/299v plus fibre (LAB) has been used for infection prevention and does not harbour the potential disadvantages of antibiotics. The objective was to assess whether LAB is not inferior to SDD in infection prevention. METHODS: Two hundred fifty-four consecutive ICU patients with expected mechanical ventilation ≥ 48 h and/or expected ICU stay ≥ 72 h were assigned to receive SDD: four times daily an oral paste (polymyxin E, gentamicin, amphotericin B), enteral solution (same antibiotics), intravenous cefotaxime (first 4 days) or LAB: two times daily L. plantarum 299/299v with rose-hip. RESULTS: The primary endpoint was infection rate. A difference <12% between both groups indicated non-inferiority of LAB. The trial was prematurely stopped after a study reporting increased mortality in critically ill pancreatitis patients receiving probiotics. No significant difference in infection rate [31% in the LAB group, 24% in the SDD group (OR 1.68, 95% CI 0.91-3.08; p = 0.10)] was found. ICU mortality was 26% and not significantly different between the LAB and SDD groups. Gram-positive cocci and Pseudomonas aeruginosa were significantly more frequently isolated from surveillance cultures in the SDD group compared to the LAB group (for sputum: 18 vs. 10% and 33 vs. 14%). Significantly more Enterobacteriaceae were found in the LAB group (23 vs. 50%). No increase in antibiotic resistance was found during and after SDD or LAB use. CONCLUSIONS: The trial could not demonstrate the non-inferiority of LAB compared with SDD in infection prevention. Results suggest no increased ICU mortality risk in the LAB group.

Staphylococcus aureus carriage among GPs in The Netherlands.

BACKGROUND: The extent to which GPs serve as a reservoir for antibiotic-resistant Staphylococcus aureus is unknown and not well studied. AIM: To determine the prevalence of nasal S. aureus carriage among GPs in the Netherlands, as well as the antimicrobial resistance and the genotypes of isolated S. aureus. DESIGN OF STUDY: Observational, point-prevalence, and cross-sectional study. SETTING: GPs attending the annual conference of the Dutch College of General Practitioners in 2006. METHOD: Nasal swabs were randomly taken from 395 GPs and analysed for the presence of S. aureus. Antimicrobial susceptibility was determined by a microbroth dilution method and the genotypes by spa typing, which was associated with multilocus sequence typing. RESULTS: Of the GPs, 129/395 (33%; 95% confidence interval [CI] = 28 to 37%) were carriers of S. aureus. No meticillin-resistant S. aureus (MRSA) was found. Resistance was observed to penicillin (71%; 95% CI = 63 to 79%), fusidic acid (7%; 95% CI = 3 to 13%), and clarithromycin (6%; 95% CI = 3 to 12%). In 72% of the isolates, an MRSA-related genotype of S. aureus was found. CONCLUSION: The low antibiotic resistance found among S. aureus of GPs suggests that GPs are not a reservoir of antibiotic-resistant S. aureus strains. The relatively high resistance to fusidic acid, which has not previously been described in the Netherlands and is mostly because of antibiotic use, suggests that patients infect GPs and not the other way round. GPs may be at risk for nasal carriage of S. aureus with an MRSA-related genotype.

Soluble Triggering Receptor Expressed on Myeloid cells-1 in bronchoalveolar lavage fluid is not predictive for ventilator-associated pneumonia.

PURPOSE: Soluble Triggering Receptor Expressed on Myeloid cells-1 (sTREM-1) has proven to be a good biomarker for sepsis. For the diagnosis ventilator-associated pneumonia (VAP), however, there have only been a few, relatively small, studies on the role of this receptor. The aim of the study was to evaluate the usefulness of sTREM-1 in bronchoalveolar lavage fluid (BALF) from Intensive Care Unit patients as rapid diagnostic test for VAP. METHODS: The concentration of sTREM-1 in 240 BALF samples was measured using a quantitative sandwich enzyme immunoassay. Two researchers who were blind to the assay results determined whether a VAP was present or not. Clinical suspicion of a VAP was confirmed by the presence of > or = 2% cells containing intracellular organisms and/or a quantitative culture result of > or = 10(4) colony forming units per millilitre BALF. RESULTS: The mean concentration of sTREM-1 was significantly higher in the BALF of patients with confirmed VAP than in that of patients without confirmed VAP. However, the area under the receiver-operating characteristic curve was 0.58 (95% confidence interval 0.50-0.65, P = 0.04). CONCLUSIONS: The results imply that the sTREM-1 assay in BALF may not be discriminative for VAP.

Different clonal complexes of methicillin-resistant Staphylococcus aureus are disseminated in the Euregio Meuse-Rhine region.

The Euregio Meuse-Rhine (EMR) is formed by the border regions of Belgium, Germany, and The Netherlands. Cross-border health care requires infection control measures, in particular since the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) differs among the three countries. To investigate the dissemination of MRSA in the EMR, 152 MRSA isolates were characterized by pulsed-field gel electrophoresis (PFGE), SCCmec typing, and multilocus sequence typing. PFGE revealed major clonal groups A, G, L, and Q, suggesting dissemination of MRSA in the EMR. Group A harbored mainly SCCmec type III and sequence types (STs) 239 and 241. The majority of the strains from group G harbored SCCmec type I and ST8 and ST247, whereas most strains from group L carried either SCCmec type IV or type I. Within group L, ST8 and ST228 were found, belonging to clonal complexes 8 and 5, respectively. Most strains from group Q included SCCmec type II and were sequence typed as ST225. Both ST225-MRSA-II and ST241-MRSA-III were novel findings in Germany. In addition, the SCCmec type of two isolates has not been described previously. One strain was classified as SCCmec type III but harbored the pls gene and the dcs region. Another strain was characterized as SCCmec type IV but lacked the dcs region. In addition, one isolate harbored both SCCmec type V and Panton-Valentine leukocidin. Finally, the SCCmec type of the strains was found to be correlated with the antibiotic susceptibility pattern.