The choice of empirical antibiotic treatment for patients with clinically suspected community-acquired pneumonia (CAP) who are admitted to non-intensive care unit (ICU) hospital wards is complicated ...by the limited availability of evidence. We compared strategies of empirical treatment (allowing deviations for medical reasons) with beta-lactam monotherapy, beta-lactam-macrolide combination therapy, or fluoroquinolone monotherapy.
In a cluster-randomized, crossover trial with strategies rotated in 4-month periods, we tested the noninferiority of the beta-lactam strategy to the beta-lactam-macrolide and fluoroquinolone strategies with respect to 90-day mortality, in an intention-to-treat analysis, using a noninferiority margin of 3 percentage points and a two-sided 90% confidence interval.
A total of 656 patients were included during the beta-lactam strategy periods, 739 during the beta-lactam-macrolide strategy periods, and 888 during the fluoroquinolone strategy periods, with rates of adherence to the strategy of 93.0%, 88.0%, and 92.7%, respectively. The median age of the patients was 70 years. The crude 90-day mortality was 9.0% (59 patients), 11.1% (82 patients), and 8.8% (78 patients), respectively, during these strategy periods. In the intention-to-treat analysis, the risk of death was higher by 1.9 percentage points (90% confidence interval CI, -0.6 to 4.4) with the beta-lactam-macrolide strategy than with the beta-lactam strategy and lower by 0.6 percentage points (90% CI, -2.8 to 1.9) with the fluoroquinolone strategy than with the beta-lactam strategy. These results indicated noninferiority of the beta-lactam strategy. The median length of hospital stay was 6 days for all strategies, and the median time to starting oral treatment was 3 days (interquartile range, 0 to 4) with the fluoroquinolone strategy and 4 days (interquartile range, 3 to 5) with the other strategies.
Among patients with clinically suspected CAP admitted to non-ICU wards, a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality. (Funded by the Netherlands Organization for Health Research and Development; CAP-START ClinicalTrials.gov number, NCT01660204.).
Risk factors for nontuberculous mycobacteria (NTM) infections after solid organ transplant (SOT) are not well characterized. Here we aimed to describe these factors.
Retrospective, multinational, 1:2 ...matched case-control study that included SOT recipients ≥12 years old diagnosed with NTM infection from 1 January 2008 to 31 December 2018. Controls were matched on transplanted organ, NTM treatment center, and post-transplant survival greater than or equal to the time to NTM diagnosis. Logistic regression on matched pairs was used to assess associations between risk factors and NTM infections.
Analyses included 85 cases and 169 controls (59% male, 88% White, median age at time of SOT of 54 years interquartile range {IQR} 40-62). NTM infection occurred in kidney (42%), lung (35%), heart and liver (11% each), and pancreas transplant recipients (1%). Median time from transplant to infection was 21.6 months (IQR 5.3-55.2). Most underlying comorbidities were evenly distributed between groups; however, cases were older at the time of NTM diagnosis, more frequently on systemic corticosteroids and had a lower lymphocyte count (all P < .05). In the multivariable model, older age at transplant (adjusted odds ratio aOR 1.04; 95 confidence interval CI, 1.01-1.07), hospital admission within 90 days (aOR, 3.14; 95% CI, 1.41-6.98), receipt of antifungals (aOR, 5.35; 95% CI, 1.7-16.91), and lymphocyte-specific antibodies (aOR, 7.73; 95% CI, 1.07-56.14), were associated with NTM infection.
Risk of NTM infection in SOT recipients was associated with older age at SOT, prior hospital admission, receipt of antifungals or lymphocyte-specific antibodies. NTM infection should be considered in SOT patients with these risk factors.
Bronchoalveolar lavage is commonly used in clinical practice for unresolved pneumonia. However, bronchoalveolar lavage is not suitable for all patients as it is an invasive procedure and can worsen ...oxygenation. The diagnostic value of bronchial wash and sputum has been debated extensively over the years. In this study, we aim to compare the diagnostic value in several pathogens of bronchoalveolar lavage and bronchial wash, and secondarily bronchoalveolar lavage and sputum.
We retrospectively included all adult patients in our hospital who underwent bronchoalveolar lavage, bronchial wash, and where sputum sampling was done between January 1st of 2018 and December 31st of 2021. The intraclass correlation coefficient was computed for the three tests.
In total, 308 patients were included. We found a level of correlation of 0.819 and 0.865, respectively, between bronchoalveolar lavage and bronchial wash for two pathogens: Staphylococcus aureus and Pseudomonas aeruginosa. For Stenotrophomonas maltophilia and Aspergillus fumigatus, we found an intraclass correlation coefficient of 0.568 and 0.624, respectively. Between bronchoalveolar lavage and sputum, we found varying levels of agreement.
Our study shows reasonably well agreement levels between bronchoalveolar lavage and bronchial wash, suggesting that bronchial wash could potentially be an alternative to bronchoalveolar lavage.
Vaccination against coronavirus disease 2019 (COVID-19) has contributed greatly to providing protection against severe disease, thereby reducing hospital admissions and deaths. Several studies have ...reported reduction in vaccine effectiveness over time against the Omicron sub-lineages. However, the willingness to receive regular booster doses in the general population is declining. To determine the need for repeated booster vaccinations in healthy individuals and to aid policymakers in future public health interventions for COVID-19, we aim to gain insight into the immunogenicity of the additional bivalent booster vaccination in a representative sample of the healthy Dutch population. The SWITCH ON study was initiated to investigate three main topics: i) immunogenicity of bivalent vaccines after priming with adenovirus- or mRNA-based vaccines, ii) immunological recall responses and reactivity with relevant variants after booster vaccination, and iii) the necessity of booster vaccinations for the healthy population in the future.
https://clinicaltrials.gov/, identifier NCT05471440.
Guidelines recommend macrolides and fluoroquinolones in patients hospitalized with community-acquired pneumonia (CAP), but their use has been associated with cardiac events. We quantified ...associations between macrolide and fluoroquinolone use and cardiac events in patients hospitalized with CAP in non-ICU wards.
This was a post-hoc analysis of a cluster-randomized trial as a cohort study; including patients with a working diagnosis of CAP admitted to non-ICU wards without a cardiac event on admission. We calculated cause-specific hazard ratio's (HR's) for effects of time-dependent macrolide and fluoroquinolone exposure as compared to beta-lactam monotherapy on cardiac events, defined as new or worsening heart failure, arrhythmia, or myocardial ischemia during hospitalization.
Cardiac events occurred in 146 (6.9%) of 2107 patients, including heart failure (n = 101, 4.8%), arrhythmia (n = 53, 2.5%), and myocardial ischemia (n = 14, 0.7%). These occurred in 11 of 207 (5.3%), 18 of 250 (7.2%), and 31 of 277 (11.2%) patients exposed to azithromycin, clarithromycin, and erythromycin for at least one day, and in 9 of 234 (3.8%), 5 of 194 (2.6%), and 23 of 566 (4.1%) exposed to ciprofloxacin, levofloxacin, and moxifloxacin, respectively. HR's for erythromycin, compared to beta-lactam monotherapy, on any cardiac event and heart failure were 1.60 (95% CI 1.09;2.36) and 1.89 (95% CI 1.22;2.91), respectively. HR's for levofloxacin and moxifloxacin, compared to beta-lactam monotherapy, on any cardiac event were 0.40 (95% CI 0.18;0.87)and 0.56 (95% CI 0.36;0.87), respectively. Findings remained consistent after adjustment for confounders and/or in a sensitivity analysis of radiologically confirmed CAP (n = 1604, 76.1%).
Among patients with CAP hospitalized to non-ICU wards, erythromycin use was associated with a 68% increased risk of hospital-acquired cardiac events, mainly heart failure. Levofloxacin and moxifloxacin were associated with a lower risk of heart failure. Although our study does not fully exclude confounding bias, findings remained largely unchanged in crude, adjusted, and sensitivity analyses. These findings may caution the use of erythromycin as empirical therapy in these patients.
The original trial was retrospectively registered under ClinicalTrials.gov Identifier NCT01660204 on August 8th, 2012.
The diagnostic yield of blood cultures is limited in patients with community-acquired pneumonia (CAP). Yet, positive blood culture results provide important information for antibiotic treatment and ...for monitoring epidemiologic trends. We investigated the potential of clinical predictors to improve the cost-benefit ratio of obtaining blood cultures.
Data from two prospective cohort studies of adults with suspected CAP, admitted to non-ICU wards, were combined. Two models were created, one using readily available parameters and one additionally including laboratory parameters.
3,786 patients were included (2,626 (69%) with X-ray confirmed CAP). Blood cultures were obtained from 2,977 (79%) patients (and from 2,107 (80%) with X-ray confirmed CAP). 266 (8.9%) of the patients with a blood culture had bacteraemia. Clinical predictors of bacteraemia were absence of pre-admission antibiotic treatment, pleuritic pain, gastro-intestinal symptoms, tachycardia, tachypnea, hypotension and absence of hypoxia. After including laboratory results in the model, younger age, C-reactive protein, leukocytosis or leukopenia, low thrombocyte count, low sodium level, elevated urea and elevated arterial pH were added, while gastro-intestinal symptoms and hypotension were no longer significant. The area under the receiver operating characteristics curve was 0.66 (95% confidence interval 0.63-0.70) for the first model and 0.76 (95% confidence interval 0.73-0.79) for the second model.
In conclusion, in patients hospitalized with CAP, bacteraemia was moderately predictable using clinical parameters only. We recommend against the use of a risk prediction model for the decision to obtain blood cultures.
Galactomannan (GM) testing of bronchoalveolar lavage (BAL) fluid samples has become an essential tool to diagnose invasive pulmonary aspergillosis (IPA) and is part of diagnostic guidelines. ...Enzyme-linked immunosorbent assays (ELISAs) (enzyme immunoassays EIAs) are commonly used, but they have a long turnaround time. In this study, we evaluated the performance of an automated chemiluminescence immunoassay (CLIA) with BAL fluid samples. This was a multicenter retrospective study in the Netherlands and Belgium. BAL fluid samples were collected from patients with underlying hematological diseases with a suspected invasive fungal infection. Diagnosis of IPA was based on the 2020 European Organisation for Research and Treatment of Cancer (EORTC)/Mycoses Study Group Education and Research Consortium (MSGERC) consensus definitions. GM results were reported as optical density index (ODI) values. ODI cutoff values for positive results that were evaluated were 0.5, 0.8, and 1.0 for the EIA and 0.16, 0.18, and 0.20 for the CLIA. Probable IPA cases were compared with two control groups, one with no evidence of IPA and another with no IPA or possible IPA. Qualitative agreement was analyzed using Cohen's κ, and quantitative agreement was analyzed by Spearman's correlation. We analyzed 141 BAL fluid samples from 141 patients; 66 patients (47%) had probable IPA, and 56 cases remained probable IPA when the EIA GM result was excluded as a criterion, because they also had positive culture and/or duplicate positive PCR results. Sixty-three patients (45%) had possible IPA and 12 (8%) had no IPA. The sensitivity and specificity of the two tests were quite comparable, and the overall qualitative agreement between EIA and CLIA results was 81 to 89%. The correlation of the actual CLIA and EIA values was strong at 0.72 (95% confidence interval, 0.63 to 0.80). CLIA has similar performance, compared to the gold-standard EIA, with the benefits of faster turnaround because batching is not required. Therefore, CLIA can be used as an alternative GM assay for BAL fluid samples.
The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) demonstrated the efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) in preventing vaccine-type community-acquired ...pneumonia and vaccine-type invasive pneumococcal disease in elderly subjects. We examined the cost-effectiveness of PCV13 vaccination in the Netherlands. Using a Markov-type model, incremental cost-effectiveness ratios (ICER) of PCV13 vaccination in different age- and risk-groups for pneumococcal disease were evaluated using a societal perspective. Estimates of quality-adjusted life-years (QALYs), costs, vaccine efficacy and epidemiological data were based on the CAPiTA study and other prospective studies. The base-case was PCV13 vaccination of adults aged 65-74 years compared to no vaccination, assuming no net indirect effects in base-case due to paediatric 10-valent pneumococcal conjugate vaccine use. Analyses for age- and risk-group specific vaccination strategies and for different levels of hypothetical herd effects from a paediatric PCV programme were also conducted. The ICER for base-case was €8650 per QALY (95% CI 5750-17,100). Vaccination of high-risk individuals aged 65-74 years was cost-saving and extension to medium-risk individuals aged 65-74 years yielded an ICER of €2900. Further extension to include medium- and high-risk individuals aged ≥18 years yielded an ICER of €3100.PCV13 vaccination is highly cost-effective in the Netherlands. The transferability of our results to other countries depends upon vaccination strategies already implemented in those countries.
Abstract
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).
This prospective multicenter study showed that real-time resistance testing may limit the impact of azole resistance on mortality. An isolated positive polymerase chain reaction assay was not associated with mortality. Its place in the current EORTC/MSGERC definitions should be reconsidered.
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