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Background: Infectious illnesses are a serious health concern in Indonesia. Widespread use of self-medication by the community increases the risk of developing multi-drug resistant (MDR) bacteria. This study assessed the potential of sappan wood as an inhibitor of extended-spectrum beta-lactamase (ESBL) encoded by blaSHV, blaTEM and blaCTX-M genes. Method: In silico testing was conducted to develop an effective and economical starting strategy. Thereby, this study significantly advances the development of novel treatments to combat antibiotic resistance. Using clavulanic acid as the benchmark medicine, the potency of the beta-lactamase inhibitor brazilein was predicted. Using the Molegro Virtual Docker computer tool, docking was performed to estimate the chemical and physical properties of the compounds, as well as the biological activity of brazilein toward the required receptor. The receptors used were SHV-1 beta-lactamase, PDB code: 2H0T; TEM-1 beta-lactamase, PDB code: 4OQG and CTX-M-14 beta-lactamase, PDB code: 6VHS. Data analysis was performed by comparing the binding energies of the docking results between the ligands and the target receptor. The more stable the bond that formed between the ligand and the target receptor, the lower the bond energy. Results: The in silico test results on the blaSHV gene were as follows: binding energy of ligand MA4_400[A] = -100.699, brazilein = -82.206, clavulanic acid = -79.3704; in the blaTEM gene: ligand bond energy 2UL_301[B] = -107.681, brazilein = -82.0296, clavulanic acid = -103.3; in the blaCTX-M gene: X57_301[A] ligand bond energy = -86.6197, and brazilein = -88.1586, clavulanic acid = -101.933. Conclusion: The findings of this study demonstrate the significant potential of brazilein sappan wood to block the beta-lactamase activity of blaCTX-M.

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It is essential to evaluate the effects of operating conditions in submerged cultures of filamentous microorganisms. In particular, the impeller type influences the flow pattern, power consumption, and energy dissipation, leading to differences in the hydrodynamic environment that affect the morphology of the microorganism. This work investigated the effect of different impeller types, namely the Rushton turbine (RT-RT) and Elephant Ear impellers in up-pumping (EEUP) and down-pumping (EEDP) modes, on cellular morphology and clavulanic acid (CA) production by Streptomyces clavuligerus in a stirred-tank bioreactor. At 800 rpm and 0.5 vvm, the cultivations performed using RT-RT and EEUP impellers provided higher shear conditions and oxygen transfer rates than those observed with EEDP. These conditions resulted in higher clavulanic acid production using RT-RT (380.7 mg/L) and EEUP (453.3 mg/L) impellers, compared to EEDP (196.6 mg/L). Although the maximum CA concentration exhibited the same order of magnitude for RT-RT and EEUP impellers, the latter presented 40% of the specific power consumption (4.9 kW/m3) compared to the classical RT-RT (12.0 kW/m3). The specific energy for CA production ( E CA ), defined as the energy cost to produce 1 mg of CA, was 3.5 times lower using the EEUP impeller (1.91 kJ/mgCA) when compared to RT-RT (5.91 kJ/mgCA). Besides, the specific energy for O2 transfer ( E O 2 ), the energy required to transfer 1 mmol of O2, was 2.3 times lower comparing the EEUP impeller (3.28 kJ/mmolO2) to RT-RT (7.65 kJ/mmolO2). The results demonstrated the importance of choosing the most suitable impeller configuration in conventional bioreactors to manufacture bioproducts.

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Clavulanic acid (CLAV) is a non-antibiotic ß-lactam that has been used since the late 1970s as a ß-lactamase inhibitor in combination with amoxicillin, another ß-lactam with antibiotic activity. Its long-observed adverse reaction profile allows it to say that CLAV is a well-tolerated drug with mainly mild adverse reactions. Interestingly, in 2005, it was discovered that ß-lactams enhance the astrocytic expression of GLT-1, a glutamate transporter essential for maintaining synaptic glutamate homeostasis involved in several pathologies of the central nervous system (CNS). This finding, along with a favorable pharmacokinetic profile, prompted the appearance of several studies that intended to evaluate the effect of CLAV in preclinical disease models. Studies have revealed that CLAV can increase GLT-1 expression in the nucleus accumbens (NAcc), medial prefrontal cortex (PFC), and spinal cord of rodents, to affect glutamate and dopaminergic neurotransmission, and exert an anti-inflammatory effect by modulating the levels of the cytokines TNF-α and interleukin 10 (IL-10). CLAV has been tested with positive results in preclinical models of epilepsy, addiction, stroke, neuropathic and inflammatory pain, dementia, Parkinson's disease, and sexual and anxiety behavior. These properties make CLAV a potential therapeutic drug if repurposed. Therefore, this review aims to gather information on CLAV's effect on preclinical neurological disease models and to give some perspectives on its potential therapeutic use in some diseases of the CNS.

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AIM: To emphasize the role of non-sulfonamides in the treatment of Nocardia infection and reduce the adverse reactions caused by sulfonamides. METHODS: We retrospectively analyzed a case of cutaneous nocardiosis in an immunocompetent individual. The colonies obtained by staining the pus in the lesion with antacid and culturing the agar plates were identified by flight mass spectrometry. The pathogenic identification showed Nocardia brasiliensis infection and the patient was treated with amoxicillin-clavulanic acid. RESULTS: After treatment with amoxicillin and clavulanic acid, the ulcer gradually peeled and crusted, leaving dark pigmentation. The patient has finally recovered. CONCLUSION: Sulfonamides are the first-line antibacterial agents for years in treatment of nocardiosis but are of great toxicity and side effects. This patient was successfully treated with amoxicillin-clavulanic acid and it provided a reference protocol for patients with sulfonamide-resistant Nocardia or sulfonamides intolerance.

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Introducción: Es importante considerar la posible implicación de microorganismos poco frecuentes en infecciones de piel y partes blandas si la muestra obtenida para cultivo es de buena calidad, y además se aísla en cultivo puro, como ocurre con Escherichia vulneris. Caso Clínico: Presentamos en caso de una mujer de 34 años, sin antecedentes mórbidos, quien desarrolló un absceso en el 4° dedo de la mano tras un traumatismo con una rama y que requirió drenaje quirúrgico y tratamiento antibiótico para su resolución. En el contenido del absceso, se aisló E. vulneris en cultivo puro, con un perfil antibiótico multisensible. Discusión y Conclusión: E. vulneris es una enterobacteria cuya patogenicidad ha estado clásicamente discutida, pero que se ha visto que puede tener participación en infección de heridas, especialmente aquellas relacionadas con material vegetal. Este microorganismo, muy relacionado con E. harmannii, presenta buena sensibilidad a los aminoglucósidos, con excepción a la penicilina y al cotrimoxazol. En las infecciones de piel y tejidos blandos causadas por E. vulneris y que cursen como un absceso, es importante realizar desbridamiento quirúrgico, si es necesario para la resolución completa del cuadro, además del tratamiento con amoxicilina/ácido clavulánico que parece adecuado.

Introduction: It is important to assess the possible involvement of rare microorganisms in skin and soft tissue infections if the sample obtained for culture is of good quality, and is isolated in pure culture, as occurs with Escherichia vulneris. Case Report: We present the case of a 34-year-old woman, with no history of morbidity, who developed an abscess in the 4th finger of the hand after trauma with a branch and which required surgical drainage and antibiotic treatment for its resolution. In the content of the abscess, E. vulneris was isolated in pure culture, with a multisensitive antibiotic profile. Discusion: E. vulneris is an Enterobacteriaceae whose pathogenicity has been classically discussed, but it has been seen that it may have participated in the infection of wounds, especially those related to plant material. This organism, closely related to E. harmannii, shows good sensitivity to aminoglycosides, with the exception of penicillin, and cotrimoxazole. In skin and soft tissue infections caused by E. vulneris and that present as an abscess, it is important to perform surgical debridement if necessary for complete resolution of the condition, in addition to treatment with amoxicillin/clavulanic acid, which seems appropriate.

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Animal bites have a high probability of becoming infected. In high-risk wounds, the use of antibiotics that kill the associated microorganisms is recommended. The aim of this study was to determine the use of inappropriate antibiotics in patients in different regions of Colombia who were attacked in 2020 by animals that can transmit rabies. This was a retrospective follow-up study of a cohort of patients with wounds caused by animals; the patients were affiliated with the Colombian Health System. Sociodemographic, clinical and pharmacological data were collected. A total of 280 patients were analysed. The median age was 28.0 years, and 52.1% were men. The attacks were attributed to dogs (85.0%) and cats (15.0%), and 9.6% were classified as severe exposure. Antibiotics were used in 71.1% of cases for prophylaxis and in 4.3% of the cases for the treatment of superinfection; cephalexin (37.5%), amoxicillin/clavulanic acid (15.7%) and dicloxacillin (10.4%) were the predominant antibiotics used. A total of 72.0% of patients who received antibiotics received inadequate prescriptions, and 49.2% had no indication to receive prophylaxis. Being treated in the Caribbean region (OR: 4.09; 95% CI: 1.79-9.30) and receiving analgesics (OR: 3.15; 95% CI: 1.25-7.94) were associated with a greater probability of being prescribed antibiotics inadequately; attacks resulting in severe exposure were associated with a lower probability (OR: 0.40; 95% CI: 0.16-0.98). A significant proportion of patients had no indication for prophylactic antibiotics or was prescribed antibiotics not recommended by clinical practice guidelines. There was a low prevalence of prescriptions for amoxicillin/clavulanic acid, the most recommended antibiotic.

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Sigma factors and sigma factor-related mechanisms control antibiotic production in Streptomyces. In this contribution, the orf21 gene was overexpressed in the wild-type strain of Streptomyces clavuligerus ATCC2764, yielding S. clavuligerus/pIORF21, to further evaluate its regulatory effect on clavulanic acid (CA) biosynthesis under different culture medium conditions. The orf21 overexpression, regulated under the constitutive promoter ermE*, led to 2.6-fold increase in CA production in GSPG medium, and a 1.8-fold decrease using ISP medium. As for GYM and MYM media, S. clavuligerus/pIORF21 strain showed higher aerial mycelium production compared to control. Glycerol uptake rate profile was affected by orf21 overexpression. Furthermore, in GSPG, S. clavuligerus/pIORF21 slightly increased the expression of adpA and gcas genes, whilst, in ISP, the claR gene expression was drastically reduced, which is consistent with a decreased CA production, observed in this medium. These findings suggest the protein encoded by the orf21 gene plays a role in the regulation of CA biosynthesis as a response to the nutritional composition of the medium.

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The emergence of metallo-ß-lactamase (MBL)-producing Enterobacterales, mainly New Delhi metallo-ß-lactamase (NDM), represents a clinical threat due to the limited therapeutic alternatives. Aztreonam (AZT) is stable to MBLs, but most MBL-producing Enterobacterales isolates usually co-harbour other ß-lactamases that confer resistance to AZT and, consequently, its use is restricted in these isolates. We compared the ability of sulbactam (SUL), tazobactam (TAZ), clavulanic acid (CLA) and avibactam (AVI) to restore the AZT activity in MBL-producing AZT-resistant Enterobacterales isolates. A collection of 64 NDM-producing AZT-resistant Enterobacterales from five hospitals in Buenos Aires city, Argentina, were studied during the period July-December 2020. MICs were determined using the agar dilution method with Mueller-Hinton agar according to Clinical and Laboratory Standards Institute (CLSI) recommendations. AVI, SUL and TAZ were used at a fixed concentration of 4 mg l-1, whereas CLA was used at a fixed concentration of 2 mg l-1. A screening method based on disc diffusion to evaluate this synergy was also conducted. Detection of bla KPC, bla OXA, bla NDM, bla VIM, bla CTXM-1, bla PER-2 and bla CIT was performed by PCR. The AZT-AVI combination restored the AZT activity in 98.4 % of AZT-resistant strains, whereas CLA, TAZ and SUL did so in 70.3, 15.6 and 12.5 %, respectively, in isolates co-harbouring extended-spectrum ß-lactamases, but were inactive in isolates harbouring AmpC-type enzymes and/or KPC. The synergy screening test showed an excellent negative predictive value to confirm the absence of synergy, but positive results should be confirmed by a quantitative method. The excellent in vitro performance of the AZT-CLA combination represents a much more economical alternative to AZT-AVI, which could be of use in the treatment of MBL-producing, AZT-resistant Enterobacterales.

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Streptomyces clavuligerus (S. clavuligerus) has been widely studied for its ability to produce clavulanic acid (CA), a potent inhibitor of ß-lactamase enzymes. In this study, S. clavuligerus cultivated in 2D rocking bioreactor in fed-batch operation produced CA at comparable rates to those observed in stirred tank bioreactors. A reduced model of S. clavuligerus metabolism was constructed by using a bottom-up approach and validated using experimental data. The reduced model was implemented for in silico studies of the metabolic scenarios arisen during the cultivations. Constraint-based analysis confirmed the interrelations between succinate, oxaloacetate, malate, pyruvate, and acetate accumulations at high CA synthesis rates in submerged cultures of S. clavuligerus. Further analysis using shadow prices provided a first view of the metabolites positive and negatively associated with the scenarios of low and high CA production.