During the last 30 years the incidence of fungal infections has increased dramatically. While the antifungal therapeutic options available are somewhat reduced, most pathogenic microorganisms have an incredible capacity to mutate and acquire resistance. In addition, multiple drugs are often required concomitantly to manage clinically complex disorders. The combination of antibiotics or other compounds with antifungal drugs, simultaneously or sequentially, is commonly adopted in clinical practice, although without a full knowledge of the consequences. Thus, the role of combined therapy and the effect of antibiotics upon fungal growth promotion need to be critically evaluated and understood in order to avoid undesirable drug interactions. With this review we intend discuss the studies that report about antibiotics inhibiting fungal growth, as well as studies describing the synergistic effect of the combined therapy, i.e., associations between antibiotics or other compounds with antifungal drugs. Alternative therapeutic protocols for fungal disease could be designed, taking advantage of such drug combinations. Critical revision of previously published data is crucial in order to define future research strategies.

Cancer is one of the most aggressive and deadly diseases in the world, representing the second leading cause of death. It is a multifactorial disease, in which genetic alterations play a key role, but several environmental factors also contribute to its development and progression. Infections induced by certain viruses, bacteria, fungi and parasites constitute risk factors for cancer, being chronic infection associated to the development of certain types of cancer. On the other hand, susceptibility to infectious diseases is higher in cancer patients. The state of the host immune system plays a crucial role in the susceptibility to both infection and cancer. Importantly, immunosuppressive cancer treatments increase the risk of infection, by decreasing the host defenses. Furthermore, alterations in the host microbiota is also a key factor in the susceptibility to develop cancer. More recently, the identification of a tumor microbiota, in which bacteria establish a symbiotic relationship with cancer cells, opened a new area of research. There is evidence demonstrating that the interaction between bacteria and cancer cells can modulate the anticancer drug response and toxicity. The present review focuses on the interaction between microbes and cancer, specifically aiming to: (1) review the main infectious agents associated with development of cancer and the role of microbiota in cancer susceptibility; (2) highlight the higher vulnerability of cancer patients to acquire infectious diseases; (3) document the relationship between cancer cells and tissue microbiota; (4) describe the role of intratumoral bacteria in the response and toxicity to cancer therapy.

The therapeutic strategies against acute myeloid leukemia (AML) have hardly been modified over four decades. Although resulting in a favorable outcome in young patients, older individuals, the most affected population, do not respond adequately to therapy. Intriguingly, the mechanisms responsible for AML cells chemoresistance/susceptibility are still elusive. Mounting evidence has shed light on the relevance of proteolytic systems (autophagy and ubiquitin-proteasome system, UPS), as well as the AMPK pathway, in AML biology and treatment, but their exact role is still controversial. Herein, two AML cell lines (HL-60 and KG-1) were exposed to conventional chemotherapeutic agents (cytarabine and/or doxorubicin) to assess the relevance of autophagy and UPS on AML cells’ response to antileukemia drugs. Our results clearly showed that the antileukemia agents target both proteolytic systems and the AMPK pathway. Doxorubicin enhanced UPS activity while drugs’ combination blocked autophagy specifically on HL-60 cells. In contrast, KG-1 cells responded in a more subtle manner to the drugs tested consistent with the higher UPS activity of these cells. In addition, the data demonstrates that autophagy may play a protective role depending on AML subtype. Specific modulators of autophagy and UPS are, therefore, promising targets for combining with standard therapeutic interventions in some AML subtypes.

Patients with multiple comorbidities are often administered simultaneously or sequentially antifungals and antibacterial agents, without full knowledge of the consequences of drug interactions. Considering the clinical relevance of liposomal amphotericin B (L-AMB), the association between L-AMB and six antibacterial agents was evaluated against four clinical isolates and one type strain of Candida spp. and two clinical isolates and one type strain of Aspergillus fumigatus. In order to evaluate such combined effects, the minimal inhibitory concentration (MIC) of L-AMB was determined in the presence of 0.5-, 1-, 2-, and 4-fold peak plasma concentrations of each of the antibacterial drugs. Since the L-AMB/colistin (CST) association was the most synergic, viability assays were performed and the physiological status induced by this association was characterized. In addition, computational molecular dynamics studies were also performed in order to clarify the molecular interaction. The maximum synergistic effect with all antibacterial agents, except CST, was reached at fourfold the usual peak plasma concentrations, resulting in 2-to 8-fold L-AMB MIC reduction for Candida and 2-to 16-fold for Aspergillus. For CST, the greatest synergism was registered at peak plasma concentration (3 mg/L), with 4-to 8-fold L-AMB MIC reduction for Candida and 16-to 32-fold for Aspergillus. L-AMB at subinhibitory concentration (0.125 mg/L) combined with CST 3 mg/L resulted in: a decrease of fungal cell viability; an increase of cell membrane permeability; an increase of cellular metabolic activity soon after 1 h of exposure, which decreased until 24 h; and an increase of ROS production up to 24 h. From the molecular dynamics studies, AMB and CST molecules shown a propensity to form a stable molecular complex in solution, conferring a recognition and binding added value for membrane intercalation. Our results demonstrate that CST interacts synergistically with L-AMB, forming a stable complex, which promotes the fungicidal activity of L-AMB at low concentration.

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Burn wound infections are often the source of bacteria responsible for systemic infections, including bloodstream infections and pneumonia that ultimately can result in multisystem organ failure and death. Any rapid change in the burn wound appearance or the clinical condition of the burn patient may herald burn wound infection or sepsis. The revival of phage therapy, either in single mode or in combination with conventional antibiotics may represent a valuable alternative, to treat specific bacterial infections such as burn wound infections, including those caused by multidrug resistant organisms. This systematic review addresses the: a) general characteristics of bacteriophages; b) activity of bacteriophages versus conventional antibiotics; c) activity of bacteriophages against biofilms; d) bacteriophage administration; and e) use of bacteriophages in burn wound infections. Although several scientific organizations/societies recognized that phage therapy could be of key value in modern wound care, specific aspects are critical for a burn surgeon and might represent pitfalls discouraging phage therapy adoption in burn wound management; in particular, the unavailability of consensual therapeutic guidelines/regulatory policies and the lack of laboratorial support that might be predictive of its efficacy. The availability of a product/formulation convenient to use, with adequate stability and shelf half-life is also a key condition.

This paper studies the Facility Layout Problem (FLP) of a first tier supplier in the automotive industry. This complex manufacturing system involves multiple facilities, complex products, and layout reconfiguration constraints. One of the key requirements of this particular system is the need for high levels of flexibility in the reconfiguration of the layouts. This problem is formulated as a mixed-integer programming (MIP), based on a FLP model with multiple objectives and unequal areas. The model allows for two reconfiguration types: small and large changes. We explore the application of optimization methodologies to produce efficient and flexible layouts.

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