Expanding antibiotic, vaccine, and diagnostics development and access to tackle antimicrobial resistance.

The increasing number of bacterial infections globally that do not respond to any available antibiotics indicates a need to invest in-and ensure access to-new antibiotics, vaccines, and diagnostics. The traditional model of drug development, which depends on substantial revenues to motivate investment, is no longer economically viable without push and pull incentives. Moreover, drugs developed through these mechanisms are unlikely to be affordable for all patients in need, particularly in low-income and middle-income countries. New, publicly funded models based on public-private partnerships could support investment in antibiotics and novel alternatives, and lower patients' out-of-pocket costs, making drugs more accessible. Cost reductions can be achieved with public goods, such as clinical trial networks and platform-based quality assurance, manufacturing, and product development support. Preserving antibiotic effectiveness relies on accurate and timely diagnosis; however scaling up diagnostics faces technological, economic, and behavioural challenges. New technologies appeared during the COVID-19 pandemic, but there is a need for a deeper understanding of market, physician, and consumer behaviour to improve the use of diagnostics in patient management. Ensuring sustainable access to antibiotics also requires infection prevention. Vaccines offer the potential to prevent infections from drug-resistant pathogens, but funding for vaccine development has been scarce in this context. The High-Level Meeting of the UN General Assembly in 2024 offers an opportunity to rethink how research and development can be reoriented to serve disease management, prevention, patient access, and antibiotic stewardship.

Clofazimine as a substitute for rifampicin improves efficacy of Mycobacterium avium pulmonary disease treatment in the hollow-fiber model.

Mycobacterium avium complex pulmonary disease is treated with an azithromycin, ethambutol, and rifampicin regimen, with limited efficacy. The role of rifampicin is controversial due to inactivity, adverse effects, and drug interactions. Here, we evaluated the efficacy of clofazimine as a substitute for rifampicin in an intracellular hollow-fiber infection model. THP-1 cells, which are monocytes isolated from peripheral blood from an acute monocytic leukemia patient, were infected with M. avium ATCC 700898 and exposed to a regimen of azithromycin and ethambutol with either rifampicin or clofazimine. Intrapulmonary pharmacokinetic profiles of azithromycin, ethambutol, and rifampicin were simulated. For clofazimine, a steady-state average concentration was targeted. Drug concentrations and bacterial densities were monitored over 21 days. Exposures to azithromycin and ethambutol were 20%-40% lower than targeted but within clinically observed ranges. Clofazimine exposures were 1.7 times higher than targeted. Until day 7, both regimens were able to maintain stasis. Thereafter, regrowth was observed for the rifampicin-containing regimen, while the clofazimine-containing regimen yielded a 2 Log10 colony forming unit (CFU) per mL decrease in bacterial load. The clofazimine regimen also successfully suppressed the emergence of macrolide tolerance. In summary, substitution of rifampicin with clofazimine in the hollow-fiber model improved the antimycobacterial activity of the regimen. Clofazimine-containing regimens merit investigation in clinical trials.

Overuse of antibiotics for urinary tract infections in pregnant refugees, Lebanon.

Objective: To determine whether adding urine culture to urinary tract infection diagnosis in pregnant women from refugee camps in Lebanon reduced unnecessary antibiotic use. Methods: We conducted a prospective, cross-sectional study between April and June 2022 involving pregnant women attending a Médecins Sans Frontières sexual reproductive health clinic in south Beirut. Women with two positive urine dipstick tests (i.e. a suspected urinary tract infection) provided urine samples for culture. Bacterial identification and antimicrobial sensitivity testing were conducted following European Committee on Antimicrobial Susceptibility Testing guidelines. We compared the characteristics of women with positive and negative urine culture findings and we calculated the proportion of antibiotics overprescribed or inappropriately used. We also estimated the cost of adding urine culture to the diagnostic algorithm. Findings: The study included 449 pregnant women with suspected urinary tract infections: 18.0% (81/449) had positive urine culture findings. If antibiotics were administered following urine dipstick results alone, 368 women would have received antibiotics unnecessarily: an overprescription rate of 82% (368/449). If administration was based on urine culture findings plus urinary tract infection symptoms, 144 of 368 women with negative urine culture findings would have received antibiotics unnecessarily: an overprescription rate of 39.1% (144/368). The additional cost of urine culture was 0.48 euros per woman. Conclusion: A high proportion of pregnant women with suspected urinary tract infections from refugee camps unnecessarily received antibiotics. Including urine culture in diagnosis, which is affordable in Lebanon, would greatly reduce antibiotic overprescription. Similar approaches could be adopted in other regions where microbiology laboratories are accessible.

Genomic characterization of methicillin-susceptible Staphylococcus aureus carriage in patients on home parenteral nutrition and their caregivers.

In this prospective study, patients on home parenteral nutrition were twice as likely to be colonized with Staphylococcus aureus if their caregivers were also carriers. Among S. aureus-positive patients and their caregivers, molecular analysis showed 68% genetically related strains. Despite decolonization, genetically related strains reappeared in 70% of patients.

Rectal Culture-Based Versus Empirical Antibiotic Prophylaxis to Prevent Infectious Complications in Men Undergoing Transrectal Prostate Biopsy: A Randomized, Nonblinded Multicenter Trial.

BACKGROUND: An increase in infections after transrectal prostate biopsy (PB), related to an increasing number of patients with ciprofloxacin-resistant rectal flora, necessitates the exploration of alternatives for the traditionally used empirical prophylaxis of ciprofloxacin. We compared infectious complication rates after transrectal PB using empirical ciprofloxacin prophylaxis versus culture-based prophylaxis. METHODS: In this nonblinded, randomized trial, between 4 April 2018 and 30 July 2021, we enrolled 1538 patients from 11 Dutch hospitals undergoing transrectal PB. After rectal swab collection, patients were randomized 1:1 to receive empirical prophylaxis with oral ciprofloxacin (control group [CG]) or culture-based prophylaxis (intervention group [IG]). Primary outcome was any infectious complication within 7 days after biopsy. Secondary outcomes were infectious complications within 30 days, and bacteremia and bacteriuria within 7 and 30 days postbiopsy. For primary outcome analysis, the χ2 test stratified for hospitals was used. Trial registration number: NCT03228108. RESULTS: Data from 1288 patients (83.7%) were available for analysis (CG, 652; IG, 636). Infection rates within 7 days postbiopsy were 4.3% (n = 28) (CG) and 2.5% (n = 16) (IG) (P value = .08; reduction: -1.8%; 95% confidence interval, -.004 to .040). Ciprofloxacin-resistant bacteria were detected in 15.2% (n = 1288). In the CG, the presence of ciprofloxacin-resistant rectal flora resulted in a 6.2-fold higher risk of early postbiopsy infection. CONCLUSIONS: Our study supports the use of culture-based prophylaxis to reduce infectious complications after transrectal PB. Despite adequate prophylaxis, postbiopsy infections can still occur. Therefore, culture-based prophylaxis must be weighed against other strategies that could reduce postbiopsy infections. Clinical Trials Registration. NCT03228108.

The role of rifampicin within the treatment of Mycobacterium avium pulmonary disease.

Rifampicin is recommended for the treatment of Mycobacterium avium complex pulmonary disease alongside azithromycin and ethambutol. We evaluated the azithromycin-ethambutol backbone with and without rifampicin in an intracellular hollow fiber model and performed RNA sequencing to study the differences in adaptation. In an in vitro hollow fiber experiment, we simulated epithelial lining fluid pharmacokinetic profiles of the recommended 3-drug (rifampicin, ethambutol, and azithromycin) or a 2-drug (ethambutol and azithromycin) treatment. THP-1 cells infected with M. avium ATCC700898 were exposed to these regimens for 21 days. We determined intra- and extra-cellular bacterial load- and THP-1 cell densities on days 0, 3, 7, 14, and 21, alongside RNA sequencing. The emergence of macrolide resistance was studied by inoculating intra- and extra-cellular fractions of azithromycin-containing Middlebrook 7H10 agar plates. Complete pharmacokinetic profiles were determined at days 0 and 21. Both therapies maintained stasis of both intra- and extra-cellular bacterial populations for 3 days, whilst regrowth coinciding with the emergence of a macrolide-resistant subpopulation was seen after 7 days. THP-1 cell density remained static. Similar transcriptional profiles were observed for both therapies that were minimally influenced by exposure duration. Transcriptional response was slightly larger during 2-drug treatment. Rifampicin did not add to the antimycobacterial effect to the 2-drug therapy or suppression of emergence resistance. RNA transcription was not greatly altered by the addition of rifampicin, which may be due to strong transcriptional influence of azithromycin and host cells. This questions the role of rifampicin in the currently recommended therapy. These findings should be confirmed in clinical trials.

MGIT Enriched Shotgun Metagenomics for Routine Identification of Nontuberculous Mycobacteria: a Route to Personalized Health Care.

Currently, nontuberculous mycobacteria (NTM) are identified using small genomic regions, and species-level identification is often not possible. We introduce a next-generation sequencing (NGS) workflow that identifies mycobacteria to (sub)species level on the basis of the whole genome extracted from enriched shotgun metagenomic data. This technique is used to study the association between genotypes and clinical manifestations to pave the way to more personalized health care. Two sets of clinical isolates (explorative set [n = 212] and validation set [n = 235]) were included. All data were analyzed using a custom pipeline called MyCodentifier. Sequences were matched against a custom hsp65 database (NGS-hsp65) and whole-genome database (NGS-WG) created based on the phylogeny presented by Tortoli et al. (E. Tortoli, T. Fedrizzi, C. J. Meehan, A. Trovato, et al., Infect Genet Evol 56:19-25, 2017, https://doi.org/10.1016/j.meegid.2017.10.013). Lastly, phylogenetic analysis was performed and correlated with clinical manifestation. In the explorative set, we observed 98.6% agreement between the line probe assay and the NGS-hsp65 database. In the validation set, 99.1% agreement between the NGS-WG and NGS-hsp65 databases was seen on the complex level. We identified a cluster of Mycobacterium marinum isolates not represented by the Tortoli et al. phylogeny. Phylogenetic analysis of M. avium complex isolates confirmed misclassification of M. timonense and M. bouchedurhonense and identified subclusters within M. avium although no correlation with clinical manifestation was observed. We performed routine NGS to identify NTM from MGIT enriched shotgun metagenomic data. Phylogenetic analyses identified subtypes of M. avium, but in our set of isolates no correlation with clinical manifestation was found. However, this NGS workflow paves a way for more personalized health care in the future.

Influenza A(H1N1)pdm09 But Not A(H3N2) Virus Infection Induces Durable Seroprotection: Results From the Ha Nam Cohort.

BACKGROUND: The extent to which influenza recurrence depends upon waning immunity from prior infection is undefined. We used antibody titers of Ha-Nam cohort participants to estimate protection curves and decay trajectories. METHODS: Households (270) participated in influenza-like-illness (ILI) surveillance and provided blood at intervals spanning laboratory-confirmed virus transmission. Sera were tested in hemagglutination inhibition assay. Infection was defined as influenza virus-positive ILI and/or seroconversion. Median protective titers were estimated using scaled-logistic regression to model pretransmission titer against infection status in that season, limiting analysis to households with infection(s). Titers were modelled against month since infection using mixed-effects linear regression to estimate decay and when titers fell below protection thresholds. RESULTS: From December 2008-2012, 295 and 314 participants were infected with H1N1pdm09-like and A/Perth/16/09-like (H3N2Pe09) viruses, respectively. The proportion protected rose more steeply with titer for H1N1pdm09 than for H3N2Pe09, and estimated 50% protection titers were 19.6 and 37.3, respectively. Postinfection titers started higher against H3N2Pe09 but decayed more steeply than against H1N1pdm09. Seroprotection was estimated to be sustained against H1N1pdm09 but to wane by 8-months for H3N2Pe09. CONCLUSIONS: Estimates indicate that infection induces durable seroprotection against H1N1pdm09 but not H3N2Pe09, which could in part account for the younger age of A(H1N1) versus A(H3N2) cases.

Endocarditis Caused by Nontypeable Streptococcus pneumoniae.

The Streptococcus pneumoniae capsule is regarded as indispensable in bacteremia. We report an infant with a ventricular septal defect and infective endocarditis caused by nontypeable S. pneumoniae. In-depth investigation confirmed a deficient capsule yet favored pneumococcal fitness for causing infective endocarditis, rather than a host immune disorder, as the cause of infective endocarditis in this case.

RNA Sequencing Elucidates Drug-Specific Mechanisms of Antibiotic Tolerance and Resistance in Mycobacterium abscessus.

Mycobacterium abscessus is an opportunistic pathogen notorious for its resistance to most classes of antibiotics and low cure rates. M. abscessus carries an array of mostly unexplored defense mechanisms. A deeper understanding of antibiotic resistance and tolerance mechanisms is pivotal in development of targeted therapeutic regimens. We provide the first description of all major transcriptional mechanisms of tolerance to all antibiotics recommended in current guidelines, using RNA sequencing-guided experiments. M. abscessus ATCC 19977 bacteria were subjected to subinhibitory concentrations of clarithromycin (CLR), amikacin (AMK), tigecycline (TIG), cefoxitin (FOX), and clofazimine (CFZ) for 4 and 24 h, followed by RNA sequencing. To confirm key mechanisms of tolerance suggested by transcriptomic responses, we performed time-kill kinetic analysis using bacteria after preexposure to CLR, AMK, or TIG for 24 h and constructed isogenic knockout and knockdown strains. To assess strain specificity, pan-genome analysis of 35 strains from all three subspecies was performed. Mycobacterium abscessus shows both drug-specific and common transcriptomic responses to antibiotic exposure. Ribosome-targeting antibiotics CLR, AMK, and TIG elicit a common response characterized by upregulation of ribosome structural genes, the WhiB7 regulon and transferases, accompanied by downregulation of respiration through NuoA-N. Exposure to any of these drugs decreases susceptibility to ribosome-targeting drugs from multiple classes. The cytochrome bd-type quinol oxidase contributes to CFZ tolerance in M. abscessus, and the sigma factor sigH but not antisigma factor MAB_3542c is involved in TIG resistance. The observed transcriptomic responses are not strain-specific, as all genes involved in tolerance, except erm(41), are found in all included strains.

The Effect of Different Types of Prostate Biopsy Techniques on Post-Biopsy Infectious Complications.

PURPOSE: The aim of our study was to compare infectious complication rates between different prostate biopsy techniques with various number of biopsy cores. MATERIALS AND METHODS: In this retrospective study, all patients from 2 hospitals who underwent prostate biopsy between 2012 and 2019 were identified. Cohorts with different types of prostate biopsies were compiled within these hospitals. Primary outcome measure was any registered infectious complication within 7 days post-biopsy. Secondary outcomes were infectious complications within 30 days, hospitalization and bacteremia. To compare the risk of infection following different prostate biopsy techniques, data was fitted into a logistic regression model adjusting for potential confounders. RESULTS: In total, 4,233 prostate biopsies in 3,707 patients were included. After systematic transrectal ultrasound-guided prostate biopsy (TRUSPB; 12±1.4 biopsy cores), 4.0% (2,607) of all patients had infectious complications within 7 days post-biopsy. Transperineal magnetic resonance imaging (MRI)-ultrasound fusion guided prostate biopsy (16±3.7 biopsy cores) was associated with significantly lower infection rates than systematic TRUSPB (adjusted OR: 0.29 [0.09-0.73] 95% confidence interval [CI]). Transrectal targeted MRI-ultrasound fusion guided prostate biopsy (3.1±0.8 biopsy cores) and transrectal targeted in-bore MRI guided prostate biopsy (2.8±0.8 biopsy cores) also showed fewer infectious complications than systematic TRUSPB (adjusted OR: 0.41 [0.12-1.12] 95% CI and 0.68 [0.37-1.20] 95% CI, respectively). CONCLUSIONS: Transperineal prostate biopsy, or transrectal prostate biopsy with reduced number of biopsy cores, could lower the risk of infectious complications.

A method comparison study of the high throughput automated HISCL® SARS-CoV-2 antigen assay using nasopharyngeal swab samples from symptomatic and asymptomatic subjects against conventional RT-PCR.

Our study aim was to evaluate the performance of the automated Sysmex HISCL® severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen assay against reverse-transcription polymerase chain reaction (RT-PCR). We tested 277 remnant frozen nasopharyngeal swab samples, stored in universal transport medium (UTM), yielding a sensitivity of 94.9% against historical RT-PCR results with cycle threshold (Ct ) < 30, and a sensitivity of 76.7% for Ct < 35, and specificity of 100% (all Ct values) confirming compatibility of UTM-diluted samples with the assay system. Thereafter, we prospectively collected 141 nasopharyngeal swab samples in UTM from healthcare workers and 1369 paired swabs (400 UTM; 969 dry) from individuals at a public health testing center, with the first swab (UTM) reserved for RT-PCR, yielding a positivity rate of 4.6%. HISCL assay performance using UTM swabs was superior to dry swabs, with a sensitivity of 100% (95% confidence interval [CI] 71.5%-100%) at Ct < 30 versus 92.3% (95%CI 81.5%-97.9%), and a specificity of 99.3% (95% CI 98.1-99.89) against 83.3% (95%CI 80.7%-85.6%). We conclude that this antigen assay is suitable for high throughput facilities where the primary indication for testing is to rule out infection with low RT-PCR Ct values (proxy for high viral loads) to curb viral spread.

The Benzimidazole SPR719 Shows Promising Concentration-Dependent Activity and Synergy against Nontuberculous Mycobacteria.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is emerging worldwide. Currently recommended multidrug treatment regimens yield poor outcomes, and new drugs and regimens are direly needed. SPR719, the active moiety of SPR720, is a new benzimidazole antibiotic with limited data on antimycobacterial activity. We determined MICs and MBCs against 138 clinical and reference strains of M. avium complex (MAC), M. kansasii, M. abscessus, M. xenopi, M. malmoense, and M. simiae and determined synergy with antimycobacterial drugs by checkerboard titrations. To study pharmacodynamics, we performed time-kill kinetics assays of SPR719 alone and in combinations against M. avium, M. kansasii, and M. abscessus and assessed synergy by response surface analysis according to Bliss independence. SPR719 showed potent activity against MAC (MIC90, 2 mg/liter) and M. kansasii (MIC90, 0.125 mg/liter) and modest activity against M. abscessus (MIC90, 8 mg/liter); its activity is bacteriostatic and concentration-dependent. We recorded a potential for combination therapy with ethambutol against M. kansasii and M. avium and synergy with clarithromycin against M. abscessus Ethambutol increased the SPR719 kill rate against M. kansasii but only prevented SPR719 resistance in M. avium SPR719 is active in vitro against NTM; its activity is strongest against M. kansasii, followed by MAC and M. abscessus SPR719 shows promise for combination therapy with ethambutol against MAC and M. kansasii and synergy with clarithromycin against M. abscessus The parent drug SPR720 could have a role especially in MAC pulmonary disease treatment. Further studies in dynamic models and trials are ongoing to advance clinical development.

An In Vitro Perspective on What Individual Antimicrobials Add to Mycobacterium avium Complex Therapies.

For Mycobacterium avium complex pulmonary disease (MAC-PD), current treatment regimens yield low cure rates. To obtain an evidence-based combination therapy, we assessed the in vitro activity of six drugs, namely, clarithromycin (CLR), rifampin (RIF), ethambutol (EMB), amikacin (AMK), clofazimine (CLO), and minocycline (MIN), alone and in combination, against Mycobacterium avium and studied the contributions of individual antibiotics to efficacy. The MICs of all antibiotics against M. avium ATCC 700898 were determined by broth microdilution. We performed kinetic time-kill assays of all single drugs and clinically relevant two-, three-, four-, and five-drug combinations against M. avium. Pharmacodynamic interactions of these combinations were assessed using area under the time-kill curve-derived effect size and Bliss independence. Adding a second drug yielded an average increase of the effect size (E) of 18.7% ± 32.9%, although antagonism was seen in some combinations. Adding a third drug showed a smaller increase in effect size (+12.2% ± 11.5%). The RIF-CLO-CLR (E of 102 log10 CFU/ml · day), RIF-AMK-CLR (E of 101 log10 CFU/ml · day), and AMK-MIN-EMB (E of 97.8 log10 CFU/ml · day) regimens proved more active than the recommended RIF-EMB-CLR regimen (E of 89.1 log10 CFU/ml · day). The addition of a fourth drug had little impact on effect size (+4.54% ± 3.08%). In vitro, several two- and three-drug regimens are as effective as the currently recommended regimen for MAC-PD. Adding a fourth drug to any regimen had little additional effect. In vitro, the most promising regimen would be RIF-AMK-macrolide or RIF-CLO-macrolide.

How are rapid diagnostic tests for infectious diseases used in clinical practice: a global survey by the International Society of Antimicrobial Chemotherapy (ISAC).

Novel rapid diagnostic tests (RDTs) offer huge potential to optimise clinical care and improve patient outcomes. In this study, we aim to assess the current patterns of use around the world, identify issues for successful implementation and suggest best practice advice on how to introduce new tests. An electronic survey was devised by the International Society of Antimicrobial Chemotherapy (ISAC) Rapid Diagnostics and Biomarkers working group focussing on the availability, structure and impact of RDTs around the world. It was circulated to ISAC members in December 2019. Results were collated according to the UN human development index (HDI). 81 responses were gathered from 31 different countries. 84% of institutions reported the availability of any test 24/7. In more developed countries, this was more for respiratory viruses, whereas in high and medium/low developed countries, it was for HIV and viral hepatitis. Only 37% of those carrying out rapid tests measured the impact. There is no 'one-size fits all' solution to RDTs: the requirements must be tailored to the healthcare setting in which they are deployed and there are many factors that should be considered prior to this.

Community-acquired bacteraemia in COVID-19 in comparison to influenza A and influenza B: a retrospective cohort study.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic in the Netherlands it was noticed that very few blood cultures from COVID-19 patients turned positive with clinically relevant bacteria. This was particularly evident in comparison to the number of positive blood cultures during previous seasonal epidemics of influenza. This observation raised questions about the occurrence and causative microorganisms of bacteraemia in COVID-19 patients, especially in the perspective of the widely reported overuse of antibiotics and the rising rate of antibiotic resistance. METHODS: We conducted a retrospective cohort study on blood culture results in influenza A, influenza B and COVID-19 patients presenting to two hospitals in the Netherlands. Our main outcome consisted of the percentage of positive blood cultures. The percentage of clinically relevant blood cultures, isolated bacteria and 30-day all-cause mortality served as our secondary outcomes. RESULTS: A total of 1331 viral episodes were analysed in 1324 patients. There was no statistically significant difference (p = 0.47) in overall occurrence of blood culture positivity in COVID-19 patients (9.0, 95% CI 6.8-11.1) in comparison to influenza A (11.4, 95% CI 7.9-14.8) and influenza B patients (10.4, 95% CI 7.1-13.7,). After correcting for the high rate of contamination, the occurrence of clinically relevant bacteraemia in COVID-19 patients amounted to 1.0% (95% CI 0.3-1.8), which was statistically significantly lower (p = 0.04) compared to influenza A patients (4.0, 95% CI 1.9-6.1) and influenza B patients (3.0, 95% CI 1.2-4.9). The most frequently identified bacterial isolates in COVID-19 patients were Escherichia coli (n = 2) and Streptococcus pneumoniae (n = 2). The overall 30-day all-cause mortality for COVID-19 patients was 28.3% (95% CI 24.9-31.7), which was statistically significantly higher (p = <.001) when compared to patients with influenza A (7.1, 95% CI 4.3-9.9) and patients with influenza B (6.4, 95% CI 3.8-9.1). CONCLUSIONS: We report a very low occurrence of community-acquired bacteraemia amongst COVID-19 patients in comparison to influenza patients. These results reinforce current clinical guidelines on antibiotic management in COVID-19, which only advise utilization of antibiotics when a bacterial co-infection is suspected.

Transcatheter aortic valve replacement during the COVID-19 pandemic-A Dutch single-center analysis.

BACKGROUND AND AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic has put an enormous strain on healthcare systems and intensive care unit (ICU) capacity, leading to suspension of most elective procedures, including transcatheter aortic valve replacement (TAVR). However, deferment of TAVR is associated with significant wait-time mortality in patients with severe aortic valve stenosis. Conversely, there is currently no data available regarding the safety and feasibility of a continued TAVR program during this unprecedented crisis. The aim of this study is to evaluate the safety and feasibility of patients undergoing TAVR during the COVID-19 pandemic in our center, with specific emphasis on COVID-19 related outcomes. METHODS: All patients who underwent TAVR in our center between February 27, 2020, and June 30, 2020, were evaluated. Clinical outcomes were described in terms of Valve Academic Research Consortium 2 definitions. Patient follow-up was done by chart review and telephone survey. RESULTS: A total of 71 patients have undergone TAVR during the study period. Median age was 80 years, 63% were men, and 25% were inpatients. Procedural success was 99%. After TAVR, 30% involved admission to the ICU, and 94% were ultimately discharged to the cardiac care unit on the same day. Two patients (3%) had confirmed COVID-19 a few days after TAVR, and both died of COVID-19 pneumonia within 2 weeks after hospital discharge. CONCLUSIONS: A continued TAVR program during the COVID-19 pandemic is feasible despite limited hospital resources. However, COVID-19 related mortality after TAVR is of concern.

Thioridazine Is an Efflux Pump Inhibitor in Mycobacterium avium Complex but of Limited Clinical Relevance.

Treatment of Mycobacterium avium complex pulmonary disease (MAC-PD) is challenging partly due to high efflux pump expression. Thioridazine might block these efflux pumps. We explore the efficacy of thioridazine against M. avium isolates using MICs, time-kill combination assays, ex vivo macrophage infection assays, and efflux assays. Thioridazine is bactericidal against M. avium, inhibits intracellular growth at 2× MIC, and blocks ethidium bromide efflux. However, its toxicity and low plasma concentrations make it unlikely to add efficacy to MAC-PD therapy.

A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis.

BACKGROUND: Talaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking. METHODS: In this open-label, noninferiority trial, we randomly assigned 440 HIV-infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all-cause mortality at week 2. Secondary outcomes included all-cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side-effect profile. RESULTS: The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], -3.9 to 5.6; P<0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P=0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group. CONCLUSIONS: Amphotericin was superior to itraconazole as initial treatment for talaromycosis with respect to 6-month mortality, clinical response, and fungicidal activity. (Funded by the Medical Research Council and others; IVAP Current Controlled Trials number, ISRCTN59144167 .).

Efficacy and safety of selective decontamination of the digestive tract (SDD) to prevent recurrent hepatic cyst infections in polycystic liver disease: a retrospective case series.

BACKGROUND: Hepatic cyst infection is a complication of polycystic liver disease (PLD) that causes substantial morbidity. Repetitive infection is frequent and is increasingly difficult to treat. As translocated gut bacteria are considered the cause, we hypothesize that selective decontamination of the digestive tract (SDD) reduces recurrence of hepatic cyst infection. METHODS: We performed a retrospective, observational study in two referral centres. All patients with PLD treated with SDD for hepatic cyst infection were included. Efficacy was determined by calculating the infection incidence (hepatic cyst infections per month) before and during SDD therapy. Adverse events were scored according to the Common Terminology Criteria for Adverse Events (CTCAE). RESULTS: We identified eight patients who received SDD (88% female, 88% polycystic kidney disease). The median age was 65 years (IQR: 51-74 years). SDD lowered the median incidence from 0.09 episodes per month (IQR: 0.06-0.25 episodes per month) to 0.01 episodes per month (IQR: 0.00-0.05 episodes per month) (P = 0.12). Discontinuation of SDD led to rapid recurrence of cyst infection (71% within 6 weeks). SDD consisted of polymyxins with/without aminoglycosides. The median SDD treatment duration was 20 months (range: 3-89 months). Six patients (75%) developed adverse events [CTCAE Grade 1 (gastrointestinal: n = 3) or Grade 3 (ototoxicity: n = 1; fungal infection: n = 1)], mostly attributable to aminoglycosides; one patient developed polymyxin E resistance. CONCLUSIONS: SDD prophylaxis provides a novel strategy for limiting recurrent hepatic cyst infection in PLD patients. However, adverse events are frequent and curtail its use. As most were attributable to aminoglycosides, polymyxin E is considered the preferred therapy.