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The understanding of antibiotic resistance, one of the major health threats of our time, is mostly based on dated and incomplete notions, especially in clinical contexts. The "canonical" mechanisms of action and pharmacodynamics of antibiotics, as well as the methods used to assess their activity upon bacteria, have not changed in decades; the same applies to the definition, acquisition, selective pressures, and drivers of resistance. As a consequence, the strategies to improve antibiotic usage and overcome resistance have ultimately failed. This review gathers most of the "non-canonical" notions on antibiotics and resistance: from the alternative mechanisms of action of antibiotics and the limitations of susceptibility testing to the wide variety of selective pressures, lateral gene transfer mechanisms, ubiquity, and societal factors maintaining resistance. Only by having a "big picture" view of the problem can adequate strategies to harness resistance be devised. These strategies must be global, addressing the many aspects that drive the increasing prevalence of resistant bacteria aside from the clinical use of antibiotics.

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection induces a spectrum of clinical manifestations that depend on the immune response of the patient, i.e., from an asymptomatic form to an inflammatory response with multiorgan deterioration. In some cases, severe cases of SARS-CoV-2 are characterized by an excessive, persistent release of inflammatory mediators known as a cytokine storm. This phenomenon arises from an ineffective T helper (Th)-1 response, which is unable to control the infection and leads to a reinforcement of innate immunity, causing tissue damage. The evolution of the disease produced by SARS-CoV2, known as COVID-19, has been of interest in several research fields. Asthma patients have been reported to present highly variable outcomes due to the heterogeneity of the disease. For example, the Th2 response in patients with allergic asthma is capable of decreasing Th1 activation in COVID-19, preventing the onset of a cytokine storm; additionally, IL-33 released by damaged epithelium in the context of COVID-19 potentiates either Th1 or T2-high responses, a process that contributes to poor outcomes. IL-13, a T2-high inflammatory cytokine, decreases the expression of angiotensin converting enzyme-2 (ACE2) receptor, hindering SARS-CoV-2 entry; finally, poor outcomes have been observed in COVID-19 patients with severe neutrophilic asthma. In other contexts, the COVID-19 lockdown has had interesting effects on asthma epidemiology. The incidence of asthma in the most populated states in Mexico, including Tamaulipas, which has the highest asthma incidence in the country, showed similar tendencies independent of how strict the lockdown measures were in each state. As described worldwide for various diseases, a decrease in asthma cases was observed during the COVID-19 lockdown. This decrease was associated with a drop in acute respiratory infection cases. The drop in cases of various diseases, such as diabetes, hypertension or depression, observed in 2020 was restored in 2022, but not for asthma and acute respiratory infections. There were slight increases in asthma cases when in-person classes resumed. In conclusion, although many factors were involved in asthma outcomes during the pandemic, it seems that acute respiratory infection is intimately linked to asthma cases. Social distancing during remote learning, particularly school lockdown, appears to be an important cause of the decrease in cases.

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Social cheating is the exploitation of public goods that are costly metabolites, like exoproteases. Exoprotease exploitation in Pseudomonas aeruginosa has been studied in reference strains. Experimental evolution with reference strains during continuous growth in casein has demonstrated that nonexoprotease producers that are lasR mutants are selected while they behave as social cheaters. However, noncanonical quorum-sensing systems exist in P. aeruginosa strains, which are diverse. In this work, the exploitation of exoproteases in the environmental strain ID4365 was evaluated; ID4365 has a nonsense mutation that precludes expression of LasR. ID4365 produces exoproteases under the control of RhlR, and harbors an inducible prophage. As expected, rhlR mutants of ID4365 behave as social cheaters, and exoprotease-deficient individuals accumulate upon continuous growth in casein. Moreover, in all continuous cultures, population collapses occur. However, this also sometimes happens before cheaters dominate. Interestingly, during growth in casein, ID4565's native prophage is induced, suggesting that the metabolic costs imposed by social cheating may increase its induction, promoting population collapses. Accordingly, lysogenization of the PAO1 lasR mutant with this prophage accelerated its collapse. These findings highlight the influence of temperate phages in social cheating.

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There are conflicting reports on the antibacterial activity of ascorbate; all at concentrations much higher than the typical in human plasma, but that can be reached in urine. The effect of 10 mM ascorbate (in itself not inhibitory) along with antibiotics, was tested both in Mueller-Hinton broth (MHb) and in synthetic human urine (SHU), against resistant isolates of Escherichia coli from lower urinary infections. The activity of nitrofurantoin and sulfamethoxazole was higher in SHU than in MHb; minimal inhibitory concentrations (MICs) in SHU with ascorbate were below typical urinary concentrations. For other antibiotics, MICs were the same in MHb vs. SHU, with no effect of ascorbate in MHb; but in SHU with ascorbate, MICs of ciprofloxacin and gentamicin also went below reported urinary concentrations, with a lesser effect with norfloxacin and trimethoprim, and none with ampicillin. The effect of ascorbate was independent of oxygen and not related to the susceptibility of each strain to oxidative stress. Ascorbate oxidizes during incubation in SHU, and bacterial growth partially prevented oxidation. These results suggest that 10 mM ascorbate can enhance the inhibitory activity of antibiotics upon resistant strains in urine. Clinical experimentation with ascorbate-antibiotic combinations against urinary infections caused by resistant bacteria is warranted.

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Macrolides inhibit biofilm formation in several Gram-negative, intrinsically-resistant bacterial species. However, the effect of macrolides upon biofilm formation by susceptible Gram-positive bacteria has been much less explored as such concentrations also inhibit cell growth. To circumvent this problem, the effect of macrolides (erythromycin, clarithromycin and azithromycin) at 0.5-2 µg/mL, upon biofilm formation, was explored on macrolide-resistant Staphylococcus aureus isolates, using the crystal violet assay with 96-well plates. Early (4 h) biofilm formation by strains having constitutive target-modification resistance was consistently induced by all macrolides but not in azithromycin-treated cells in longer (8 and 12 h) incubation. In inducible-resistance isolates, early biofilm formation was enhanced by some macrolide treatments, compared to similar cell growth in the absence of antibiotics; but the typical decay of biofilms at longer incubation appeared prematurely in macrolide-treated cultures. Biofilm formation in an efflux-mediated resistant isolate was not affected by macrolides. These results indicate that macrolides induce the formation of biofilm by resistant S. aureus isolates, especially during the early stages. This suggests that the empirical use of macrolides against infections caused by resistant S. aureus strains could not only result in clinical failure but even in the enhancement of biofilms, making further treatment difficult.

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The antibiotic resistance arena is fraught with myths and misconceptions, leading to wrong strategies to combat it. It is crucial to identify them, discuss them in light of current evidence, and dispel those that are unequivocally wrong. This article proposes some concepts that may qualify as misconceptions around antibiotic resistance: the susceptible-resistant dichotomy; that incomplete antibiotic courses cause resistance; that resistance "emerges" in patients and hospitals; that antibiotics are mostly abused clinically; that resistance is higher in countries that use more antibiotics; that reducing antibiotic usage would reduce resistance; that financial incentives would "jumpstart" research and development of antibiotics; that generic and "original" antibiotics are the same; and that new anti-infective therapies are just around the corner. While some of these issues are still controversial, it is important to recognize their controversial status, instead of repeating them in specialized literature and lectures and, especially, in the planning of strategies to cope with resistance.

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The use of phages as therapeutic or prophylactic approaches is gaining increased interest amid the growing menace of antibiotic resistance. Phages, along with other new anti-infective strategies, are certainly welcome as much needed additions to the medicinal arsenal. However, we can easily make with phages the same mistakes we made with antibiotics, which caused the current resistance crisis. The oversimplification of the ecological role of antibiotics, neglecting ancient resistance and the role of horizontal gene transfer; the active search for wide spectrum, and the massive agricultural abuse; and, most importantly, the financial greed behind the development and use of antibiotics; these are all trends that are now visible in phage research. Should we bring phages to the same track that wasted antibiotics, we could be looking at a "postphage era" in our near future.

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While monitoring the presence of antibiotic resistance in municipal wastewater bacteria from Mexico City, five Escherichia coli isolates were found to be resistant to carbapenems, antibiotics of "last resort" used mostly in hospitals. Further analysis revealed that these carbapenem-resistant isolates carried the gene encoding a metallo-beta-lactamase, NDM-5. The gene was found to be beared by a large, ∼145 kb conjugative plasmid, which also carries putative genes encoding resistance to sulfonamides, trimethoprim, tetracycline, ciprofloxacin, and chloramphenicol (although no phenotypic chloramphenicol resistance was detected) and quaternary-ammonium compounds. The plasmid also carried gene mobility determinants, such as integron integrase and two transposases. In addition to the direct public health threat posed by the presence of such multi-resistant organisms in wastewater released into the environment and used for crop irrigation; it is particularly concerning that carbapenem-resistant E. coli is rather rare in Mexican hospitals (<1%), but was found in small, 100 mL samples of municipal wastewater. This suggests that these organisms are under-reported by clinical microbiology laboratories, underlining the usefulness of wastewater monitoring, or that there is an unknown source of such carbapenem-resistant organisms that are being dumped into the wastewater. The source of these bacteria must be assessed and controlled to prevent further spread of this multi-resistance plasmid among other environmental and clinical microorganisms.

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Ten years ago, a review on the status of resistance in Mexico was bleak: with antibiotics freely sold over the counter and poor regulation of generic drugs, among other conditions, resistance among relevant pathogens often ranked top, either among Latin American countries, or even worldwide. Since then, there have been some regulatory changes, along a decline in antibiotics usage: antibiotics are (supposedly) no longer sold without prescription, generic drugs (supposedly) have to demonstrate bioequivalence, and antibiotic usage has drop, from about 13 defined daily doses per 1,000 inhabitants per day, to 7. While these changes may sound encouraging, an analysis show that regulatory changes are incomplete at best, and usage decline may be the consequence of factors such as growing poverty. The assessment of resistance continues to be haphazard, without an organized network of laboratories providing a coherent picture. However, judging from a few nationwide reports, it appears that resistance among some nosocomial pathogens (MRSA, enterococci, Pseudomonas aeruginosa) is declining, as it is among pneumococci and enteropathogens; but it is rising among community-acquired, uropathogenic Escherichia coli. Resistance to colistin is slowly increasing; and worrisome resistance determinants, such as blaNDM-1 and mcr-1, appeared in Mexico shortly after their first report elsewhere. After four years from the United Nations General Assembly high-level meeting on antibiotic resistance, Mexico is yet to deploy the basic measures to assess and control antibiotic resistance. As such, and despite the regulatory changes, the 2010-2020 period looks like a "lost decade".

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OBJECTIVE: We aimed to replicate a prior Spanish study of medication adherence where logistic regression models provided highly significant odds ratios (ORs) for three continuous scores: necessity, concern and the necessity-concern differential, and a dichotomous variable: skeptical attitude. Adherence ORs in the necessity-concern framework were very strong in patients taking five or six medications. METHODS: The sample comprised consecutive adult psychiatric outpatients in Mendoza, Argentina. The necessity-concerns framework was assessed using a subscale of the Beliefs about Medicines Questionnaire. Adherence (yes/no) to prescribed psychiatric medications was assessed by the Sidorkiewicz adherence tool. RESULTS: When compared with the Spanish sample, the Argentinian group (508 patients with 875 medications) was characterized by: (1) significantly stronger adherence ORs with the necessity-concern framework, (2) significantly lower number of medications per patient and percentage of patients with marked psychiatric polypharmacy (≥4 medications), (3) though a higher number of medications still was significantly associated with poor adherence. CONCLUSIONS: The Argentinian sample replicated the previous finding that patient beliefs regarding necessity and concern were associated with poor adherence to prescribed medications. Polypharmacy had an additive role decreasing adherence in both samples. In both samples, when prescribed ≥4 psychiatric medications, patients reported adherence to only two-third of the medications.

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Resumen: Las suspensiones comerciales de propofol, por su composición farmacéutica, soportan el crecimiento de diversos microorganismos; la aplicación de propofol, contaminado microbianamente luego de ser retirado de su envase original, ha sido vinculada a brotes de infección postoperatoria. La adición de sales de ácido etilendiaminotetraacético (EDTA) retarda el crecimiento de estos microorganismos. Aquí se comparó el crecimiento, a lo largo de 48 horas y en tres temperaturas (ambiente, 35 y 42 oC), de siete cepas bacterianas y tres de levaduras, en cuatro formulaciones de propofol disponibles en México, una de ellas adicionada con EDTA. Consistentemente, el crecimiento fue menor en la suspensión con EDTA, comparada con las tres que no lo contienen, con variaciones entre microorganismos y temperaturas: desde muerte inicial de parte del inóculo, o inhibición completa y sostenida del crecimiento, hasta inhibición parcial. Aunque la adición de EDTA no debe considerarse como un sustituto del manejo aséptico del propofol, que debe extenderse durante el período perioperatorio, ciertamente disminuye la proliferación microbiana que puede darse por contaminación accidental, disminuyendo asimismo el riesgo de infección para el paciente.

Abstract: Commercially available propofol suspensions, due to their pharmaceutical composition, support the growth of several microorganisms; the administration of propofol suspensions that became microbially-contaminated after being removed from their original vial, has been linked to postsurgical infections. Addition of ethylenediaminetetracetic acid (EDTA) salts delays the growth of such microorganisms. Here, we compared the growth of seven bacterial strains and three yeast strains, along 48 hours and at three different incubation temperatures (room temperature, 35 and 42 oC), in four propofol formulations available in Mexico, one of them with supplemented EDTA. Consistently, microbial growth was diminished in the formulation supplemented with EDTA, compared to the other three, although with variations between microorganisms and incubation temperatures: from initial reduction in viable organisms, to complete and sustained growth inhibition, to only partial growth inhibition. While the addition of EDTA to propofol suspensions must not be considered as a substitute for aseptic handling of the drug, it certainly diminishes microbial growth that can occur after accidental contamination, reducing the infection risk for the patient.

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OBJECTIVE: The aim of this study was to examine whether or not cultural differences influence beliefs about the necessity of taking prescribed psychiatric drugs and concern about their adverse effects in psychiatric outpatients in Spain, Argentina, and Venezuela. METHODS: This cross-sectional study included 1,372 adult psychiatric outpatients using 2,438 psychotropic drugs and was designed to assess outpatients' beliefs about their prescribed medication. Patients completed sociodemographic, clinical questionnaires, and the Beliefs about Medicines Questionnaire Specific Scale and registered scores ranging from 1 to 5 on each of two subscales: concern and necessity. A "necessity-concern differential" was obtained by calculating the difference (range -4 to +4). RESULTS: The global score, including all drugs in the total sample, had a mean necessity score of 3.50 ± 0.95, a mean concern score of 2.97 ± 0.99, and a mean differential score of 0.54 ± 1.42. The concern and necessity mean scores varied significantly across these three culturally Hispanic countries, probably across drug classes, and were associated with treatment duration. On the other hand, age and education played a very limited role. CONCLUSIONS: Understanding the diverse effects of culture and society on these attitudes is highly relevant for the development of responsive mental health services in multicultural societies.

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BACKGROUND: Cultural differences in attitudes toward psychiatric medications influence medication adherence but transcultural studies are missing. The objective of this study was to investigate how attitudes and beliefs toward psychotropic medications influence treatment adherence in psychiatric outpatients in Spain, Argentina, and Venezuela. METHODS: A cross-sectional, cross-cultural psychopharmacology study was designed to assess psychiatric outpatients' attitudes toward their prescribed medication. Patients completed the Drug Attitude Inventory - 10 Item (DAI-10), the Beliefs about Medicines Questionnaire - Specific Scale (BMQ-Specific), the Sidorkiewicz adherence tool, and sociodemographic and clinical questionnaires. The study included 1,291 adult psychiatric outpatients using 2,308 psychotropic drugs from three Spanish-speaking countries, the Canary Islands (Spain) (N=588 patients), Argentina (N=508), and Venezuela (N=195). RESULTS: The univariate analyses showed different mean scores on the DAI-10 and the BMQ - Necessity and Concerns subscales but, on the other hand, the percentages of non-adherent and skeptical patients were relatively similar in three countries. Argentinian patients had a very low level of pharmacophobia. Multivariate analyses (logistic regression and chi-squared automatic interaction detector segmentation) showed that pharmacophobia in general and skepticism about specific medications (high concern about adverse reactions and low belief in their necessity) were associated with non-adherence. Pharmacophobia was the major factor associated with non-adherence (Spain and Venezuela) but when pharmacophobia was rare (Argentina), skepticism was the most important variable associated with non-adherence. CONCLUSION: Psychiatric patients' attitudes and beliefs about their psychiatric treatment varied in these three Spanish-speaking countries, but pharmacophobia and skepticism appeared to play a consistent role in lack of adherence.

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Resumen OBJETIVO: Determinar la asociación entre telorragia y cáncer de mama en población mexicana atendida en una unidad médica de alta concentración. MATERIALES Y MÉTODOS: Estudio observacional, retrospectivo y analítico efectuado en pacientes con telorragia atendidas entre enero de 2007 y diciembre de 2016 en la Fundación de Cáncer de Mama (FUCAM). Se efectuó el cálculo de proporciones y un subanálisis "tipo nodo" entre telorragia más nódulo versus telorragia sola, mediante χ2, riesgo relativo e intervalo de confianza al 95% con el paquete estadístico SPSS 23.0. RESULTADOS: Se estudiaron 169 pacientes, 42 de ellas con diagnóstico definitivo de cáncer de mama. La telorragia se asoció en 24.8% con cáncer, y cuando estuvo asociada con un nódulo la probabilidad de malignidad fue de 63%. Al comparar los subgrupos: telorragia más nódulo vs telorragia sola, se encontró una razón de momios de 4.2 para el primer grupo (IC95%: 2.5-6.8; p < 0.001). CONCLUSIONES: Este estudio demostró que la probabilidad de malignidad en los casos de telorragia sola en población mexicana, en un hospital de referencia, se encuentra en el límite alto en relación con el histórico mundial, y cuando se asocia con un nódulo la probabilidad es significativamente mayor.

Absract OBJECTIVE: To determine the association between telorragia and breast cancer in a Mexican population in a highly concentrated Medical Unit. MATERIALS AND METHODS: Observational, retrospective, analytical study in patients with telorragia treated at FUCAM from January 2007 to December 2016. Proportion calculation and a "node type" sub-analysis were carried out, between telorragia plus nodule versus telorragia alone, by means of χ2, relative risk, and 95% confidence interval with statistical package SPSS 23.0. RESULTS: 169 patients were studied, 42 of them presented a definitive diagnosis of breast cancer. The telorragia was associated in 24.8% to cancer, and when it was associated with nodule the probability of malignancy was 63%. When comparing the subgroups with more nodule vs telorrhagia alone, an OR of 4.2 was found for the first group (95% CI 2.5-6.8, p <0.001). CONCLUSIONS: This study showed that the probability of malignancy in cases of telorrhagia alone in the Mexican population in a referral hospital is in the high range in relation to the historical world, and is associated with a nodule, the probability is significantly higher.

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Prosopis juliflora is a shrub that has been used to feed animals and humans. However, a synergistic action of piperidine alkaloids has been suggested to be responsible for neurotoxic damage observed in animals. We investigated the involvement of programmed cell death (PCD) and autophagy on the mechanism of cell death induced by a total extract (TAE) of alkaloids and fraction (F32) from P. juliflora leaves composed majoritary of juliprosopine in a model of neuron/glial cell co-culture. We saw that TAE (30 µg/mL) and F32 (7.5 µg/mL) induced reduction in ATP levels and changes in mitochondrial membrane potential at 12 h exposure. Moreover, TAE and F32 induced caspase-9 activation, nuclear condensation and neuronal death at 16 h exposure. After 4 h, they induced autophagy characterized by decreases of P62 protein level, increase of LC3II expression and increase in number of GFP-LC3 cells. Interestingly, we demonstrated that inhibition of autophagy by bafilomycin and vinblastine increased the cell death induced by TAE and autophagy induced by serum deprivation and rapamycin reduced cell death induced by F32 at 24 h. These results indicate that the mechanism neural cell death induced by these alkaloids involves PCD via caspase-9 activation and autophagy, which seems to be an important protective mechanism.

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ABSTRACT Prosopis juliflora is a shrub that has been used to feed animals and humans. However, a synergistic action of piperidine alkaloids has been suggested to be responsible for neurotoxic damage observed in animals. We investigated the involvement of programmed cell death (PCD) and autophagy on the mechanism of cell death induced by a total extract (TAE) of alkaloids and fraction (F32) from P. juliflora leaves composed majoritary of juliprosopine in a model of neuron/glial cell co-culture. We saw that TAE (30 µg/mL) and F32 (7.5 µg/mL) induced reduction in ATP levels and changes in mitochondrial membrane potential at 12 h exposure. Moreover, TAE and F32 induced caspase-9 activation, nuclear condensation and neuronal death at 16 h exposure. After 4 h, they induced autophagy characterized by decreases of P62 protein level, increase of LC3II expression and increase in number of GFP-LC3 cells. Interestingly, we demonstrated that inhibition of autophagy by bafilomycin and vinblastine increased the cell death induced by TAE and autophagy induced by serum deprivation and rapamycin reduced cell death induced by F32 at 24 h. These results indicate that the mechanism neural cell death induced by these alkaloids involves PCD via caspase-9 activation and autophagy, which seems to be an important protective mechanism.

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