Repurposing antibiotic resistance surveillance data to support treatment of recurrent infections in a remote setting.

In northern Australia, a region with limited access to healthcare and a substantial population living remotely, antibiotic resistance adds to the complexity of treating infections. Focussing on Escherichia coli urinary tract infections (UTIs) and Staphylococcus aureus skin & soft tissue infections (SSTIs) captured by a northern Australian antibiotic resistance surveillance system, we used logistic regression to investigate predictors of a subsequent resistant isolate during the same infection episode. We also investigated predictors of recurrent infection. Our analysis included 98,651 E. coli isolates and 121,755 S. aureus isolates from 70,851 patients between January 2007 and June 2020. Following an initially susceptible E. coli UTI, subsequent recovery of a cefazolin (8%) or ampicillin (13%) -resistant isolate during the same infection episode was more common than a ceftriaxone-resistant isolate (2%). For an initially susceptible S. aureus SSTI, subsequent recovery of a methicillin-resistant isolate (8%) was more common than a trimethoprim-sulfamethoxazole-resistant isolate (2%). For UTIs and SSTIs, prior infection with a resistant pathogen was a strong predictor of both recurrent infection and resistance in future infection episodes. This multi-centre study demonstrates an association between antibiotic resistance and an increased likelihood of recurrent infection. Particularly in remote areas, a patient's past antibiograms should guide current treatment choices since recurrent infection will most likely be at least as resistant as previous infection episodes. Using population-level surveillance data in this way can also help clinicians decide if they should switch antibiotics for patients with ongoing symptoms, while waiting for diagnostic results.

Comparison of Doxycycline or Minocycline to Sulfamethoxazole-Trimethoprim for Treatment of Stenotrophomonas maltophilia Pneumonia.

BACKGROUND: Stenotrophomonas maltophilia is a multidrug-resistant organism with limited antibiotic treatment options. Minocycline and doxycycline may be appropriate, but clinical data are limited. OBJECTIVE: To compare tetracyclines (minocycline and doxycycline [TCN]) with standard of care, sulfamethoxazole-trimethoprim (TMP-SMZ), in S. maltophilia pneumonia treatment. METHODS: This retrospective, 2-center study evaluated patients treated for S. maltophilia pneumonia with TCN or TMP-SMZ for clinical success, defined as resolution of leukocytosis, fever, and tachypnea. Patients were classified as treatment with TCN or TMP-SMZ based on definitive agent used for ≥50% of the treatment course and ≥4 days. Inclusion criteria were age ≥18 years, S. maltophilia confirmed on respiratory culture from January 2013 to November 2020, and appropriate definitive antibiotic dosing. Pregnancy, incarceration, S. maltophilia-resistant or intermediate to definitive therapy, and combination therapy for treatment of S. maltophilia pneumonia were exclusion criteria. Secondary outcomes were microbiologic success and recurrence or reinfection within 30 days requiring treatment. RESULTS: A total of 80 patients were included (21 TCN [15 minocycline, 6 doxycycline], 59 TMP-SMZ). There was no difference in clinical success (28.6% vs 25.4%; P = 0.994), microbiologic success (n = 28, 55.6% vs 66.4%; P = 0.677), or recurrence or reinfection (n = 24, 66.7% vs 26.7%; P = 0.092) between TCN and TMP-SMZ, respectively. CONCLUSION AND RELEVANCE: Clinical and microbiologic success rates were similar in patients treated with TCN compared with TMP-SMZ for S. maltophilia pneumonia. These data suggest minocycline and doxycycline may be options to treat S. maltophilia pneumonia, but conclusive clinical data continue to be lacking.

Topical formulations containing Trichilia catigua extract as therapeutic options for a genital and an acyclovir-resistant strain of herpes recurrent infection.

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infect, respectively, 67% and 13% of the world population, most commonly causing mild symptoms, such as blisters/ulcers. However, severe conditions such as keratitis, encephalitis, and systemic infections may occur, generally associated with the patient's immunological condition. Although Acyclovir® (ACV) and its analogs are the reference drugs for herpetic infections, the number of ACV-resistant HSV infections is growing exponentially. Therefore, new natural products' bioactive compounds have been studied to develop novel effective anti-herpetics. Trichilia catigua is a plant widely used in traditional medicine, including the treatment of skin diseases and sexual infections. In our study, 16 extracts from the bark of T. catigua, obtained with different solvents and their combinations, were evaluated against HSV-1 AR and HSV-2, respectively, ACV resistance and genital strains in vitro. The extracts with the highest selectivity index were used to prepare new topical anti-herpetic formulations and confirmed in vivo. Two new topical formulations were suggested to treat cutaneous and genital herpetic recurrent lesions. The cytotoxicity and antiviral activity were tested using the MTT method. The cytotoxic (CC50) and inhibitory (IC50) concentrations of 50% and the selectivity index (SI: CC50/IC50) were determined. Tc12, Tc13, and Tc16 were added to the formulations. Infected BALB/c mice were treated for 8 days, and the severity of the herpetic lesions was analyzed daily. All CEs showed a CC50 value ranging from 143 to 400 µg/mL, except for Tc3 and Tc10. Tc12, Tc13, and Tc16 showed the best SI in the 0 h, virucidal, and adsorption inhibition assays. In the in vivo test against HSV-1 AR, the infected animals treated with creams were statistically different from the infected non-treated animals and similar to ACV-treated mice. In HSV-2-infected genitalia, similar effects were found for Tc13 and Tc16 gels. The present study demonstrated that extracts from the bark of T. catigua, traditionally used in folk medicine, are a valuable source of active compounds with anti-herpetic activity. The extracts showed a virucidal mechanism of action and prevented the initial stages of viral replication. The cutaneous and genital infections were strongly inhibited by the Tc12, Tc13, and Tc16 extracts. New topical therapeutic alternatives using Trichilia catigua extracts are suggested for patients infected with ACV-resistant strains of HSV.

Red palm olein-enriched biscuit supplementation lowers Ascaris lumbricoides reinfection at 6-month after anthelmintic treatment among schoolchildren with vitamin A deficiency (VAD).

Notwithstanding the global efforts made to control intestinal parasitic infections, soil-transmitted helminth (STH) infections are still one of the most prevalent infections globally, especially in developing countries. A double-blinded, randomized controlled trial was conducted on 343 primary schoolchildren (8-12 years old) with vitamin A deficiency (VAD) in rural areas of Malaysia to investigate the effects of red palm olein (RPO)-enriched biscuits on STH reinfection rates and infection intensities. The effects of the RPO-enriched biscuits (experimental group, n = 153) and palm olein (PO)-enriched biscuits (control group, n = 190), were assessed at 3- and 6-month after the administration of complete triple-dose albendazole (one dose of 400 mg for three consecutive days). The overall STH infection rate at baseline was recorded at 65.6%. At 6-month, a significantly lower reinfection rate of A. lumbricoides was observed in the experimental group (35.3%) compared to the control group (60.0%) (P< 0.05), and a significant reduction in fecal egg count (epg) of A. lumbricoides was observed in the experimental group from baseline (P< 0.001), but no significant reduction was observed in the control group. No significant differences in the reduction of infection intensities of T. trichiura and hookworm were observed between experimental and control groups at 3- and 6-month (P>0.05). These findings suggest the potential beneficial effects of RPO-enriched biscuit supplementation on the reinfection of A. lumbricoides, which could be attributed to its high carotenoids content by enhancing host immune response and mucosal epithelium integrity. However, further studies are warranted to confirm whether RPO supplementation could result in similar parasite-specific beneficial effects in other community settings, as well as to explore the underlying mechanisms.

The Effects of Antimicrobial Resistance and the Compatibility of Initial Antibiotic Treatment on Clinical Outcomes in Patients With Diabetic Foot Infection.

We aimed to determine pathogen microorganisms, their antimicrobial resistance patterns, and the effect of initial treatment on clinical outcomes in patients with diabetic foot infection (DFI). Patients with DFI from 5 centers were included in this multicenter observational prospective study between June 2018 and June 2019. Multivariate analysis was performed for the predictors of reinfection/death and major amputation. A total of 284 patients were recorded. Of whom, 193 (68%) were male and the median age was 59.9 ± 11.3 years. One hundred nineteen (41.9%) patients had amputations, as the minor (n = 83, 29.2%) or major (n = 36, 12.7%). The mortality rate was 1.7% with 4 deaths. A total of 247 microorganisms were isolated from 200 patients. The most common microorganisms were Staphylococcus aureus (n = 36, 14.6%) and Escherichia coli (n = 32, 13.0%). Methicillin resistance rates were 19.4% and 69.6% in S aureus and coagulase-negative Staphylococcus spp., respectively. Multidrug-resistant Pseudomonas aeruginosa was detected in 4 of 22 (18.2%) isolates. Extended-spectrum beta-lactamase-producing Gram-negative bacteria were detected in 20 (38.5%) isolates of E coli (14 of 32) and Klebsiella spp. (6 of 20). When the initial treatment was inappropriate, Klebsiella spp. related reinfection within 1 to 3 months was observed more frequently. Polymicrobial infection (p = .043) and vancomycin treatment (p = .007) were independent predictors of reinfection/death. Multivariate analysis revealed vascular insufficiency (p = .004), hospital readmission (p = .009), C-reactive protein > 130 mg/dL (p = .007), and receiving carbapenems (p = .005) as independent predictors of major amputation. Our results justify the importance of using appropriate narrow-spectrum empirical antimicrobials because higher rates of reinfection and major amputation were found even in the use of broad-spectrum antimicrobials.

Evaluation of the healing potential of short-term ozone therapy for the treatment of diabetic foot ulcers.

Background: The availability of research on short-term ozone therapy for diabetic foot ulcers (DFUs) is limited, and even when it is accessible, it mainly comprises of basic analysis conducted during long-term ozone therapy. This study was to evaluate the efficacy of short-term ozone therapy in promoting wound healing in DFUs. Methods: A retrospective analysis was conducted on 89 patients with type 2 diabetes complicated by DFUs. The patients were divided into two groups: ozone therapy group (n=41) and control group (n=48). Wound condition, change of bacterial types, changes in inflammatory indicators (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and procalcitonin [PCT]), vascular endothelial growth factor (VEGF), cytokines [Interleukin 6 (IL-6) and tumor necrosis factor-α(TNF-α)], and oxidative stress levels (superoxide dismutase [SOD], malondialdehyde [MDA], and total antioxidant capacity [T-AOC]) were observed pre-treatment and after 1 week. After a 12-week of follow-up, wound healing rate, amputation rate, inpatient day, duration of antibiotics, reinfection rate, incidence of new ulcers, readmission rate, and reoperation rate, and cumulative wound healing rate using Kaplan-Meier curves were assessed. Results: After 1 week of treatment, the ozone therapy group showed higher VEGF, SOD, and T-AOC levels compared to the control group (P<0.05), while CRP, PCT, ESR, IL-6, TNF-α, MDA levels and bacterial types were lower (P<0.05). The ozone therapy group had a higher wound healing rate after a 12-week follow-up (P<0.05). Kaplan-Meier curves indicated a higher cumulative wound healing rate in the ozone therapy group (P<0.05). Additionally, the ozone therapy group had lower inpatient day, duration of antibiotics, reinfection rate, and readmission rate compared to the control group (P<0.05). Conclusion: Short-term ozone therapy is effective in promoting wound healing in DFUs by reducing inflammation, increasing growth factor levels, improving oxidative stress status, shortening healing time, and improving long-term prognosis. These findings suggest the potential of short-term ozone therapy as a valuable treatment modality for DFUs.

O itinerário terapêutico dos sobreviventes da Covid-19 / The therapeutic itinerary of Covid-19 survivors

Resumo: Anunciado pela Organização Mundial da Saúde no início de janeiro de 2020, o novo coronavírus, com altos níveis de transmissibilidade e letalidade, tornou-se uma pandemia, desafiando a ciência e os governos mundiais. Trata-se de um estudo de natureza qualitativa, de abordagem descritiva e exploratória, com a questão norteadora: como ocorreu o itinerário terapêutico dos sobreviventes das formas graves da COVID-19, no município de Itapiranga/SC? Pesquisa aprovada pelo Comitê de Ética em Pesquisa em Seres Humanos, com parecer nº 5.163.229. O referencial teórico adotado foram os Sistemas de Cuidado em Saúde de Arthur Kleinman, composto por três esferas; popular, profissional e folk. Com os objetivos de conhecer o itinerário terapêutico de pessoas sobreviventes que desenvolveram a forma grave da COVID-19, no município de Itapiranga, no estado de Santa Catarina; caracterizar os sobreviventes que desenvolveram a forma grave da COVID-19; identificar os sistemas de cuidado à saúde utilizados pelos sobreviventes da COVID-19; identificar os cuidados à saúde realizados pelos sobreviventes da COVID-19. Participaram 10 sobreviventes da COVID-19 grave. A coleta de dados foi realizada entre abril e maio de 2022, através de entrevista semiestruturada gravada em áudio. Para análise de dados utilizou-se o método de análise de conteúdo com codificação de forma manual. Os resultados evidenciaram que oito eram de sexo masculino; sete foram intubados, porém todos estiveram hospitalizados na UTI por COVID- 19. A faixa etária variou de 26 e 65 anos. As comorbidades encontradas foram hipertensão arterial sistêmica, diabetes mellitus e sobrepeso. Os sintomas iniciais apresentados: febre, tosse, mal-estar, cefaleia e alterações gastrointestinais e no agravamento com tosse, dispneia, febre, cansaço e hemoptise. O início dos sintomas até a hospitalização variou entre 4 e 14 dias. Após a internação, a evolução para intubação ou internação em UTI ocorreu na média de 6 dias. O tempo de hospitalização foi de 13 a 34 dias. As esferas de cuidado acessadas foram; popular, folk e profissional. Da análise das narrativas surgiram as seguintes categorias: Percepções do adoecimento repentino; esfera popular e a práxis do autocuidado; esfera profissional e a busca pela resolutividade; esfera profissional e a vivência da COVID-19 grave; transcendência como fonte de melhora e restauração; da fase aguda para as sequelas imprevisíveis. O início da doença foi marcado pela rotulagem e cuidados populares. A esfera profissional foi responsável pelo diagnóstico e vivências mais impactantes relacionadas à hospitalização na UTI. A prática de busca por auxílio espiritual por meio de orações marcou a esfera folk. Considera-se que no itinerário terapêutico o uso concomitante das três esferas foi representado pela influência que a cultura exerce no processo saúde-doença e sua interligação com o sistema de cuidado à saúde.

Abstract: The World Health Organization announced the new coronavirus in early January 2020, with high levels of transmissibility and lethality, which has become a pandemic, challenging science and world governments. It is a qualitative study, with a descriptive and exploratory approach, with the guiding question: how did the therapeutic itinerary of survivors of the severe forms of COVID-19 occur, in the municipality of Itapiranga/SC? The research was approved by the Ethics Committee for Research in Human Beings with opinion number 5.163.229. The theoretical reference adopted was Arthur Kleinman's Health Care Systems, composed of three spheres: popular, professional and folk. The objectives were: to know the therapeutic itinerary of survivors who developed the severe form of COVID-19, in the municipality of Itapiranga, in the state of Santa Catarina; to characterize the survivors who developed the severe form of COVID-19; to identify the health care systems used by survivors of COVID-19; to identify the health care carried out by survivors of COVID-19. Ten survivors of severe COVID-19 participated. Data collection was conducted between April and May 2022, through audio-recorded semistructured interview. For data analysis, the content analysis method was used with manual coding. The results showed that eight were male; seven were intubated, but all were hospitalized in the ICU for COVID-19. The age ranged from 26 to 65 years. The comorbidities found were systemic arterial hypertension, diabetes mellitus and overweight. The initial symptoms presented: fever, cough, malaise, headache, and gastrointestinal changes, and in aggravation with cough, dyspnea, fever, fatigue, and hemoptysis. The onset of symptoms until hospitalization ranged from 4 to 14 days. After hospitalization, the evolution to intubation or ICU admission occurred in an average of 6 days. The length of hospital stay ranged from 13 to 34 days. The spheres of care accessed were; popular, folk and professional. From the analysis of the narratives the following categories emerged: Perceptions of the sudden illness; folk sphere and the practice of self-care; professional sphere and the search for resoluteness; professional sphere and the experience of severe COVID-19; transcendence as a source of improvement and restoration; from the acute phase to the unpredictable sequelae. The onset of the disease was marked by popular labeling and care. The professional sphere was responsible for the most impactful diagnosis and experiences related to ICU hospitalization. The practice of seeking spiritual help through prayers marked the folk sphere. It is considered that in the therapeutic itinerary the concomitant use of the three spheres was represented by the influence that culture exerts on the health-disease process and its interconnection with the health care system.

Increased ShTAL1 IgE responses post-Praziquantel treatment may be associated with a reduced risk to re-infection in a Ghanaian S. haematobium-endemic community.

BACKGROUND: Evidence from recent studies in Schistosoma mansoni-endemic areas show an age-associated immunity that is positively correlated with IgE titres to Schistosoma mansoni-specific tegumental allergen-like protein 1 (SmTAL1). The structural homology between SmTAL1 and the S. haematobium-specific TAL1 (ShTAL1) has been verified, yet it remains unclear whether similar age- and immune-associated trends characterize ShTAL1. This community-based intervention study was conducted to assess whether ShTAL1IgE responses post-treatment with praziquantel (PZQ) might be associated with a reduced risk to re-infection with S. haematobium. METHODOLOGY/PRINCIPAL FINDINGS: This study was conducted at Agona Abodom, Central Region, Ghana, and involved 114 participants aged 6 to 55 years. EDTA blood samples were collected at baseline and 7 weeks after PZQ treatment (Follow-up). Baseline and Follow-up titres of specific IgG1, IgG4, and IgE antibodies to the S. haematobium-specific adult worm antigen (ShAWA), the Sh-specific soluble egg antigen (ShSEA), and the Sh-specific tegumental-allergen-like 1 protein (ShTAL1) in plasma samples were measured using sandwich ELISA. Participants at both time points also provided stool and urine for helminth egg detection by microscopy. Prevalence of S. haematobium at baseline was 22.80%, and decreased to 3.50% at Follow-up. The egg reduction rate (ERR) was 99.87%. Overall plasma levels of ShTAL1-IgE increased 7 weeks post-PZQ treatment, and with increasing age; whiles S. haematobium infection prevalence and intensity decreased. For S. haematobium-infected participants who were egg-negative at Follow-up (N = 23), minimal median levels of ShTAL1-IgE were observed for all age groups prior to treatment, whilst median levels increased considerably among participants aged 12 years and older at Follow-up; and remained minimal among participants aged 11 years or less. In the univariate analysis, being aged 12 years or older implied an increased likelihood for ShTAL1-IgE positivity [12-14 years (cOR = 9.64, 95% CI = 2.09-44.51; p = 0.004); 15+ years (cOR = 14.26, 95% CI = 3.10-65.51; p = 0.001)], and this remained significant after adjusting for confounders [12-14 years (aOR = 22.34, 95% CI = 2.77-180.14; p = 0.004); ≥15 years (aOR = 51.82, 95% CI = 6.44-417.17; p < 0.001)]. Conversely, median ShTAL1-IgG4 titres were hardly detectible at Follow-up. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate that increased IgE levels to ShTAL1 7 weeks after PZQ treatment could be associated with a reduced risk to re-infection, and adds to the large body of evidence suggesting a protective role of the treatment-induced ShTAL1 antigen in schistosomiasis infections. It was also quite clear from this work that apart from being persistently S. haematobium-positive, elevated ShTAL1-IgG4 levels at Follow-up could be indicative of susceptibility to re-infection. These outcomes have important implications in vaccine development, and in shifting the paradigm in mass chemotherapy programmes from a 'one-size-fits-all' approach to more sub-group-/participant-specific strategies in endemic areas.

Minimizing treatment-induced emergence of antibiotic resistance in bacterial infections.

Treatment of bacterial infections currently focuses on choosing an antibiotic that matches a pathogen's susceptibility, with less attention paid to the risk that even susceptibility-matched treatments can fail as a result of resistance emerging in response to treatment. Combining whole-genome sequencing of 1113 pre- and posttreatment bacterial isolates with machine-learning analysis of 140,349 urinary tract infections and 7365 wound infections, we found that treatment-induced emergence of resistance could be predicted and minimized at the individual-patient level. Emergence of resistance was common and driven not by de novo resistance evolution but by rapid reinfection with a different strain resistant to the prescribed antibiotic. As most infections are seeded from a patient's own microbiota, these resistance-gaining recurrences can be predicted using the patient's past infection history and minimized by machine learning-personalized antibiotic recommendations, offering a means to reduce the emergence and spread of resistant pathogens.

Alternativas aos antibióticos na profilaxia das infecções urinárias recorrentes não complicadas na mulher / Alternatives to antibiotics in the prophylaxis of recurrent uncomplicated infections in women

A infecção do trato urinário (ITU) é a doença bacteriana mais comum no sexo feminino, e cerca de 25% a 30% das mulheres apresentam ITUs recorrentes ao longo da vida. Os antibióticos são muito utilizados para o tratamento e prevenção dessas infecções. Entretanto, o uso excessivo e indevido desses medicamentos, além dos efeitos adversos, está relacionado ao surgimento de uropatógenos multirresistentes. Há um interesse crescente na comunidade científica para encontrar alternativas ao uso de antibióticos para tratamento e/ou prevenção das infecções bacterianas. Esta revisão tem por objetivo discutir algumas dessas alternativas.(AU)

Urinary tract infection (UTI) is the most common bacterial disease in females, and about 25% to 30% of women experience recurrent UTIs throughout their lives. Antibiotics are widely used standard for treating and preventing these infections. However, the excessive and improper use of these drugs, in addition to the adverse effects, is related to the emergence of multidrug-resistant uropathogens. There is a growing interest in the scientific community to find alternatives to the use of antibiotics for the treatment and/or prevention of bacterial infections. This review aims to discuss some of these alternatives.(AU)

HCV RNA quantification in capillary dried blood spots with the Xpert® HCV Viral Load test for diagnosing chronic HCV infection, monitoring treatment and detecting reinfection.

BACKGROUND: For patients with difficult venous access after long-term intravenous drug use, rapid point-of-care hepatitis C virus (HCV) RNA quantification in capillary whole blood with the Xpert® HCV Viral Load Fingerstick (VL FS) test (60 minutes) is a convenient and reliable method for diagnosing chronic HCV infection, monitoring treatment and detecting reinfection. However, an expensive GeneXpert® system must be available on site. In decentralised settings with a low case-load, dried blood spot (DBS) testing might be an alternative. METHODS: Between December 2019 and January 2021, patients with an indication for HCV RNA quantification and informed consent provided 100 µl capillary whole blood each for on-site Xpert® HCV VL FS testing (reference) and DBS testing in the laboratory. For the latter, 100 µl blood, collected with an EDTA Minivette®, were transferred to a Whatman® 903 filter card. After drying for at least 1 hour, the DBS sample was packed into a sealable plastic bag with desiccant and sent to the central laboratory of our hospital, where it was stored at -20°C. For HCV RNA extraction, the whole DBS was cut out with an 18-mm puncher and transferred into 1.3 ml guanidinium thiocyanate-containing buffer (provided by Cepheid®). After mixing and incubating at room temperature for 2-3 hours, 1 ml supernatant was analysed with the Xpert® HCV VL test (105 minutes) (filter paper absorbs 0.3 ml). RESULTS: Of 109 paired samples from 67 patients, 38 (34.9%) were positive with the Xpert® HCV VL FS test. Sensitivity and specificity of DBS testing were 89.5% (34/38; 95% confidence interval [CI] 75.9-95.8%) and 97.2% (69/71; 95% CI 90.3-99.2%), respectively. The six (5.5%) discordant results (four false negative, two false positive) all were observed in samples with HCV RNA detectable below the limit of quantification after 2-8 weeks of pan-genotypic direct-acting antiviral treatment or 5 weeks after acute hepatitis C in a patient clearing HCV spontaneously. Quantifiable results (n = 30; 16 genotype 1, 7 genotype 3, 4 genotype 4, 1 genotype 1a and 3a, 2 unknown; HCV RNA range: 2.74-6.66 log IU/ml) correlated well (R2 = 0.981). On average, uncorrected DBS test results were 1.30 ± 0.14 log IU/ml lower than Xpert® HCV VL FS test results (~42 µl instead of the expected 1000 µl plasma used). Storage of DBS samples at room temperature for 7 days before freezing reduced HCV RNA by 0.29 ± 0.12 log IU/ml. CONCLUSION: HCV RNA can reliably be quantified with the Xpert® HCV VL test in capillary dried blood spot samples. Thus, access to capillary HCV RNA quantification for diagnosing chronic HCV infection, monitoring treatment and detecting reinfection can be extended to decentralised settings with a low case load.

Emergence of additional drug resistance during treatment of multidrug-resistant tuberculosis in China: a prospective cohort study.

OBJECTIVES: Little is known about how additional second-line drug resistance emerges during multidrug-resistant tuberculosis (MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed infection on second-line drug resistance during the recommended 2-year MDR-TB treatment. METHODS: Individuals with MDR-TB were enrolled between 2013 and 2016 in a multicentre prospective observational cohort study and were followed up for 2 years until treatment completion. Whole-genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed infection in the development of second-line drug resistance. RESULTS: Of the 286 enrolled patients with MDR-TB, 63 (22.0%) M. tuberculosis isolates developed additional drug resistance during the MDR-TB treatment, including 5 that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41 (65.1%) of the cases of additional second-line drug resistance were the result of exogenous reinfection, 18 (28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4 (6.3%) were caused by mixed infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment (adjusted hazard ratio (aHR) 2.51, 95% CI 1.51-4.18), extensive disease on chest X-ray (aHR 3.39, 95% CI 2.03-5.66) and type 2 diabetes mellitus (aHR 4.00, 95% CI 2.22-7.21) were independent risk factors associated with the development of additional second-line drug resistance. CONCLUSIONS: A large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need for repeated drug susceptibility testing throughout MDR-TB treatment.

Limited effects of long-term daily cranberry consumption on the gut microbiome in a placebo-controlled study of women with recurrent urinary tract infections.

BACKGROUND: Urinary tract infections (UTIs) affect 15 million women each year in the United States, with > 20% experiencing frequent recurrent UTIs. A recent placebo-controlled clinical trial found a 39% reduction in UTI symptoms among recurrent UTI sufferers who consumed a daily cranberry beverage for 24 weeks. Using metagenomic sequencing of stool from a subset of these trial participants, we assessed the impact of cranberry consumption on the gut microbiota, a reservoir for UTI-causing pathogens such as Escherichia coli, which causes > 80% of UTIs. RESULTS: The overall taxonomic composition, community diversity, carriage of functional pathways and gene families, and relative abundances of the vast majority of observed bacterial taxa, including E. coli, were not changed significantly by cranberry consumption. However, one unnamed Flavonifractor species (OTU41), which represented ≤1% of the overall metagenome, was significantly less abundant in cranberry consumers compared to placebo at trial completion. Given Flavonifractor's association with negative human health effects, we sought to determine OTU41 characteristic genes that may explain its differential abundance and/or relationship to key host functions. Using comparative genomic and metagenomic techniques, we identified genes in OTU41 related to transport and metabolism of various compounds, including tryptophan and cobalamin, which have been shown to play roles in host-microbe interactions. CONCLUSION: While our results indicated that cranberry juice consumption had little impact on global measures of the microbiome, we found one unnamed Flavonifractor species differed significantly between study arms. This suggests further studies are needed to assess the role of cranberry consumption and Flavonifractor in health and wellbeing in the context of recurrent UTI. TRIAL REGISTRATION: Clinical trial registration number: ClinicalTrials.gov NCT01776021 .

Antibody response and therapy in COVID-19 patients: what can be learned for vaccine development?

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection is lacking, and different therapeutic strategies are under testing. Host humoral and cellular immunity to SARS-CoV-2 infection is a critical determinant for patients' outcomes. SARS-CoV-2 infection results in seroconversion and production of anti-SARS-CoV-2 antibodies. The antibodies may suppress viral replication through neutralization but might also participate in COVID-19 pathogenesis through a process termed antibody-dependent enhancement. Rapid progress has been made in the research of antibody response and therapy in COVID-19 patients, including characterization of the clinical features of antibody responses in different populations infected by SARS-CoV-2, treatment of COVID-19 patients with convalescent plasma and intravenous immunoglobin products, isolation and characterization of a large panel of monoclonal neutralizing antibodies and early clinical testing, as well as clinical results from several COVID-19 vaccine candidates. In this review, we summarize the recent progress and discuss the implications of these findings in vaccine development.

Mode of action of a formulation containing hydrazones and saponins against leishmania spp. Role in mitochondria, proteases and reinfection process.

Toxicity and poor adherence to treatment that favors the generation of resistance in the Leishmania parasites highlight the need to develop better alternatives. Here, we evaluated the in vitro effectiveness of hydrazone derived from chromanes 2-(2,3-dihydro-4H-1-benzothiopyran-4-ylidene) hydrazide (TC1) and 2-(2,3-dihydro-4H-1-benzopyran-4-ylidene) hydrazide (TC2) and the mixture of triterpene saponin hederagenin-3-O-(3,4-O-diacetyl-ß-D-xylopyranosyl-(1à3)-a-L- rhamnopyranosyl-(1à2)-a-L-arabinofuranoside, hederagenin-3-O-(3,4-O-diacetyl-a-L- arabinopyranosyl-(1à3)-a-L-rhamnopyranosyl-(1à2)-a-L-arabinofuranoside and, hederagenin-3-O-(4-O-acetyl-ß-D-xylopyranosyl-(1à3)-a-L-rhamnopyranosyl-(1à2)-a-L-arabinofuranoside from Sapindus saponaria (SS) on L. braziliensis and L. pifanoi. Mixtures of TC1 or TC2 with saponin were formulated for topical application and the therapeutic effectiveness was evaluated in the model for cutaneous leishmaniasis (CL) in golden hamster. The mode of action of these compounds was tested on various parasite processes and ultrastructural parasite modifications. TC1, TC2 and SS showed moderate cytotoxicity when tested independently but toxicity was improved when tested in combination. The compounds were more active against intracellular Leishmania amastigotes. In vivo studies showed that combinations of TC1 or TC2 with SS in 1:1 ratio (w/w) cured 100% of hamsters with no signs associated with toxicity. The compounds did cause changes in the mitochondrial activity of the parasite with a decrease in ATP levels and depolarization of membrane potential and overproduction of reactive oxygen species; nevertheless, these effects were not related to alterations in membrane permeability. The phagolysosome ultrastructure was also affected impacting the survival of Leishmania but the function of the lysosome nor the pH inside the phagolysosome did not change. Lastly, there was a protease inhibition which was directly related to the decrease in the ability of Leishmania to infect and multiply inside the macrophage. The results suggest that the combination of TC1 and TC2 with SS in a 1:1 ratio is capable of curing CL in hamsters. This effect may be due to the ability of these compounds to affect parasite survival and the ability to infect new cells.

Efficacy and safety of oral administration of a product based on hydroxytyrosol as preventive therapy for recurrent vulvo-vaginal candidosis: a prospective observational pilot study.

OBJECTIVE: The aim of the study is to evaluate the efficacy and safety of hydroxytyrosol for the prevention of the vulvar vaginal candida infections recurrence. PATIENTS AND METHODS: This study is a prospective observational pilot study. Eligible subjects were at least 18 years old, with at least 4 documented episodes of vulvovaginal candidiasis in the last 12 months. Patients were instructed to therapy (2 tabs daily for the first month and then 1 tab daily for 2 other months). Each capsule consists of hydroxytyrosol (HT) and other components: tea tree oil, tabebuia, juglans regia, and copper. Clinical and microbiological assessments took place at baseline and 12 weeks after. The impact on Quality of Life (QoL) was evaluated with the SF-36 and the Patient Global Impression of Improvement (PGI-I) after 3 months of treatment was calculated. RESULTS: Sixty patients were enrolled in the study. In the last 1 year the mean number of previous infections was 5.83 ± 2.76. Forty-nine patients (83%) did not have candida episodes during 3 months of treatment. A significant reduction in clinical symptoms, vaginal signs, such as pruritus, burning and vulvar erythema (< 0.0001). The SF-36 showed a significant change (55.67±8.43 vs. 84.56±11.56, p < 0.0001) and the total success at PGI-I was reported in 54 patients (90%). CONCLUSIONS: The HT-based product is effective and safe in preventing recurrent candida episodes and improves the quality of life and sexual function of treated women.

Effects of D-Mannose, ElliroseTM and Lactobacillus Plantarum in treatment of urinary tract recurrent infections (rUTIs): A survey of urologists knowledge about its clinical application.

BACKGROUND AND AIM OF THE WORK: Urinary tract infections (UTIs) and recurrent urinary tract infections (rUTIs) are widespread disease and almost half of all women will experience at least one episode of cystitis during their life. Aim of this study was to review the evidence of literature about the therapeutic and preventive effects of a product containing D-Mannose, ElliroseTM and Lactobacollus Plantarum on patients' symptoms, quality of life and recurrence of UTIs and to investigate the practicing urologists' knowledge about the clinical application of this product. MATERIALS: We administrated an investigational survey about clinical use of a phytotherapeutic product made of D-Mannose, ElliroseTM and Lactobacollus Plantarum to 12 residents in Urology at the University of Modena and Reggio Emilia and to 32 urologists working in the provinces of Modena, Reggio Emilia and Parma. RESULTS: 61% of physicians have diagnosed rUTIs in 3-6 patients during a month, and 7% of them in more than 6 patients during the same period of time. By these results rUTIs appear as common pathological conditions. 59% prescribed the product at least 1 time a month and 14% prescribed it more than 5 times. 43% administrated the product after out-patient invasive examinations as cistoscopy and urodynamic exam for UTIs prevention. 55% noticed a significant improvement in patient's QoL (Quality of Life) suffering from rUTIs. Furthermore 48% also reported a significant effect for the improvement of urinary symptoms of patients. No gastric or general side effects have been noticed during the administration period. Finally the cost of integrator has been reported affordable for the great majority of patients. CONCLUSIONS: Many studies in Literature have shown that D-Mannose and H. sabdariffa (ElliroseTM) reduce the risk of development of rUTIs opposing colonization and proliferation of uropathogenic bacteria in urinary tract. Our investigational survey about the administration of a phytotherapeutic product showed that this product is well-known and has a proved positive impact.