Epidemic territorial spread of IncP-2-type VIM-2 carbapenemase-encoding megaplasmids in nosocomial Pseudomonas aeruginosa populations [Epidemiology and Surveillance]

xloma.fota13 shared this article with you from Inoreader Epidemic territorial spread of IncP-2-type VIM-2 carbapenemase-encoding megaplasmids in nosocomial Pseudomonas aeruginosa populations [Epidemiology and Surveillance] Via AAC Accepts: Articles Published Ahead of Print In 2003-04 first five VIM-2 metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa (MPPA) isolates with an In4-like integron In461 (aadB–blaVIM-2–aadA6) on conjugative plasmids were identified in three hospitals in Poland. In 2005-15 MPPA much expanded in the country, and as many as 80 isolates in a collection of 454 MPPA (~18%) had In461, being one of two most common MBL-encoding integrons. The organisms occurred in 49 hospitals in 33 cities of 11/16 main administrative regions. PFGE and MLST classified them into 55 pulsotypes and 35 STs, respectively, revealing their remarkable genetic diversity overall, with only a few small clonal clusters. The S1 nuclease/hybridization assays and mating of 63 representative isolates showed that ~85% of these had large In461-carrying plasmids of ~350-550 kb, usually self-transmitting with high efficiency (~10–1-10–2 per donor cell). The plasmids fr om 19 isolates were sequenced, and subjected to structural and SNP-based phylogenetic analysis. These formed a subgroup within a family of IncP-2-type megaplasmids, observed worldwide in pseudomonads from various environments and conferring resistance/tolerance to multiple stress factors, including antibiotics. Their microdiversity in Poland arose mainly from acquisition of different accessory fragments, as well as new resistance genes and multiplication of these. Short-read sequence and/or PCR mapping confirmed the In461-carrying plasmids in the remaining isolates to be the IncP-2 types. The study demonstrated a large-scale epidemic spread of multi-drug resistance plasmids in P. aeruginosa populations, creating an epidemiological threat. It contributes to the knowledge on IncP-2 types, which are interesting research objects in resistance epidemiology, environmental microbiology and biotechnology. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Parasite-host dynamics throughout antimalarial drug development stages complicate the translation of parasite clearance [Pharmacology]

xloma.fota13 shared this article with you from Inoreader Parasite-host dynamics throughout antimalarial drug development stages complicate the translation of parasite clearance [Pharmacology] Via AAC Accepts: Articles Published Ahead of Print Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes pre-clinical murine and experimental human malaria infection studies to evaluate drug efficacy. A sequential approach is typically adapted, with results from each stage, informing the design of the next stage of development. The validity of this approach depends on confidence that results from murine malarial studies predict the outcome of clinical trials in humans. Parasite clearance rates following treatment are key parameters of drug efficacy. To investigate the validity of forward predictions, we developed a suite of mathematical models to capture parasite growth and drug clearance along the drug development pathway and estimated parasite clearance rates. When comparing the three infection experiments, we identified different relationships of parasite clearance with dose, and different maximum parasite clearance rates: in P. be rghei-NMRI mouse infections we estimated a maximum parasite clearance rate of 0.2 [1/h]; in P. falciparum-SCID mouse infections 0.05 [1/h]; while in human volunteer infection studies with P. falciparum, we found a maximum parasite clearance rate of 0.12 [1/h] and 0.18 [1/h] after treatment with OZ439 and MMV048, respectively. Sensitivity analysis revealed that host-parasite driven processes account for up to 25% of variance in parasite clearance for medium-high doses of antimalarials. Although there are limitations in translating parasite clearance rates across these experiments, they provide insight into characterising key parameters of drug action and dose response, and assist in decision-making regarding dosage for further drug development. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Pharmacokinetic study of rectal artesunate in children with severe malaria in Africa [Pharmacology]

xloma.fota13 shared this article with you from Inoreader Pharmacokinetic study of rectal artesunate in children with severe malaria in Africa [Pharmacology] Via AAC Accepts: Articles Published Ahead of Print When severe malaria is suspected in children, WHO recommends pre-treatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, cross-over clinical trial in 83 Congolese children with severe falciparum malaria, to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg) followed 12 hours later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at eleven fixed intervals, following 0- and 12-hour drug administrations. Clinical, laboratory and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large inter-individual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients however, reached previously suggested in vivo IC50 (98.7%) and IC90 (92.5%) values of combined concentrations of artesunate and dihydroartemisinin between 15 to 30 minutes after drug administration. The median (IQR) time above IC50 and IC90 was 5.68 hours (2.90-6.08) and 2.74 hours (1.52-3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7-54.5) for artesunate and 19.8% (10.3-35.3) for dihydroartemisinin. The initial 12-hour parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR) 84.3% (50.0-95.4) vs. 69.2% (45.7-93.6), respectively (p=0.49). Despite large inter-individual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe falciparum malaria, while they are transferred to a facility where parenteral artesunate is available. (www.clinicalTrials.gov : NCT02492178) View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistant Rv0678 mutant in a mouse model of tuberculosis [Experimental Therapeutics]

xloma.fota13 shared this article with you from Inoreader Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistant Rv0678 mutant in a mouse model of tuberculosis [Experimental Therapeutics] Via AAC Accepts: Articles Published Ahead of Print Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Clinical reports of emerging BDQ resistance have identified mutations in Rv0678 that de-repress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2-8x MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 has greater in vitro potency than BDQ, including against Rv0678 mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that against wild-type M. tuberculosis H37Rv and an isogenic Rv0678 mutant, TBAJ-587 has greater efficacy against both strains than BDQ, whether alone or in combination with pretomanid and either linezolid or moxifloxacin and pyrazinamide. TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Alteration in the Acute Kidney Injury Potential with the Combination of Vancomycin and Imipenem-Cilastatin/Relebactam or Piperacillin/Tazobactam in a Preclinical Model [Pharmacology]

xloma.fota13 shared this article with you from Inoreader Alteration in the Acute Kidney Injury Potential with the Combination of Vancomycin and Imipenem-Cilastatin/Relebactam or Piperacillin/Tazobactam in a Preclinical Model [Pharmacology] Via AAC Accepts: Articles Published Ahead of Print Background: This risk of vancomycin (VAN)-associated acute kidney injury (AKI) may be altered with combination regimens. The specific AKI risk when VAN is combined with imipenem-cilastatin/relebactam (IMP-C/REL) or piperacillin/tazobactam (TZP) has not been clearly defined. Objectives: To quantify the dose-AKI relationships of VAN alone and in combination with TZP or imipenem-cilastatin/relebactam (IMP-C/REL). Methods: Ten to twelve week old male C57BL/6J mice (Charles River Laboratory) we re dosed with study drug regimens in three stages. Stage 1 consisted of a VAN dose-ranging design (0-600 mg/kg/day) over a 7-day period to identify the VAN monotherapy dose-AKI relationship in the murine model. Stage 2 evaluated the approximate VAN dose eliciting 50% AKI response in Stage 1 in combination with the highest human equivalent doses (HED) used in pre-clinical murine models (2.5 g/kg/day of TZP, 320 mg/kg/day of IMP-C/REL). Stage 3 tested these combinations with fractionated doses of TZP or IMP-C/REL administered at 6- and 12-hour intervals. In these studies, AKI was defined both by biomarkers (serum creatinine [SCr], blood urea nitrogen [BUN]) and histopathological assessment by a treatment-blinded pathologist. Results: VAN doses of 300 to 500 mg/kg/day reproducibly led to development of AKI within 4 days of dosing. Mice treated with VAN alone had a near doubling of their baseline SCr and BUN compared to control, IMP-C/REL alone, or TZP alone. Both VAN+IMP-C /REL and VAN+TZP had significantly (p<0.05) lower SCr and BUN values compared to VAN alone when dosed once daily. This nephroprotective effect was retained with VAN+IMP-C/REL, but not VAN+TZP, when IMP-C/REL and TZP were administered every 6 hours. Biomarker results were concordant with histopathologic findings. Conclusions: The VAN dose-AKI relationship can be attenuated with single daily HEDs of TZP or IMP-C/REL in mice. IMP-C/REL, but not TZP, retained a nephroprotective effect compared to VAN monotherapy when administered as fractionated doses. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Bictegravir+tenofovir alafenamide nanoformulation with prolonged sustained-drug-release potency for HIV-1 PrEP: A concept evaluation study. [Antiviral Agents]

xloma.fota13 shared this article with you from Inoreader A new combination bictegravir+tenofovir alafenamide nanoformulation with prolonged sustained-drug-release potency for HIV-1 PrEP: A concept evaluation study. [Antiviral Agents] Via AAC Accepts: Articles Published Ahead of Print The antiretroviral treatment (ART) approach is the best-prescribed approach to date for pre-exposure prophylaxis (PrEP) for high-risk individuals. However, the daily combination ARVs (cARVs) regimen has become cumbersome for healthy individuals leading to non-adherence. Recent surveys showed high acceptance of parenteral sustained-release ART enhancing PrEP adherence. Our approach is to design a parenteral nanoparticle (NP)-based cARV sustained-release (cARV-SR) system as long-acting HIV PrEP. In this work, we reported a new combination of two potent ARV, (tenofovir alafenamide fumarate (TAF) and bictegravir (BIC)) loaded nanoformulation intended as cARV-SR for PrEP. The BIC+TAF NPs were fabricated by standardized in-house methodology. In-vitro intracellular kinetics, cytotoxicity, and HIV-1 protection studies demonstrated BIC+TAF encapsulation prolonged drug retention, reduced drug-associated cytotoxicity, and enhanced HIV protection. In human PBMCs, nanoformulated BIC+TAF demonstrated significant (p < 0.05) improvement in the drug's selectivity index by 472 times compared to the BIC+TAF in solution. In-vivo pharmacokinetic (PK) study of BIC, TAF and respective drug metabolite in female BALB/c mice after single subcutaneous BIC+TAF NPs demonstrated plasma drug concentrations of BIC and tenofovir (TFV) above intracellular IC50 level during the entire 30-day study period, and prolonged persistence of both active drugs in the HIV target organs including vagina, colon, spleen, and lymph nodes. This report demonstrated encapsulation of BIC+TAF in a nanoformulation improved its therapeutic selectivity and in-vivo pharmacokinetics of free drugs. Based on these preliminary studies, we hypothesize cARV-SR has potential as an innovative once monthly delivery for PrEP. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cefiderocol Against Stenotrophomonas maltophilia

xloma.fota13 shared this article with you from Inoreader In Vitro Activity and In Vivo Efficacy of Cefiderocol Against Stenotrophomonas maltophilia [Experimental Therapeutics] Via AAC Accepts: Articles Published Ahead of Print Cefiderocol is a novel siderophore cephalosporin antibiotic with broad coverage against difficult-to-treat Gram-negative bacteria, including those resistant to carbapenems. Its activity against Stenotrophomonas maltophilia was investigated in vitro against clinical isolates and in lung infection models using strains either resistant (SR202006) or susceptible (SR201934, SR200614) to trimethoprim/sulfamethoxazole. Cefiderocol demonstrated potent in vitro activity against all 217 S. maltophilia cl inical isolates tested (MIC50: 0.063 μg/mL, MIC90: 0.25 μg/mL). Cefiderocol also demonstrated low MICs against the trimethoprim/sulfamethoxazole-resistant S. maltophilia strains (i.e. SR202006: MIC=0.125 μg/mL). In a neutropenic mouse lung infection model, cefiderocol (30 mg/kg and 100 mg/kg) demonstrated a significant, dose-dependent reduction in the lung viable bacteria cell count compared with untreated controls in S. maltophilia infection and was the only antibiotic tested to show a similar significant effect in a trimethoprim/sulfamethoxazole-resistant S. maltophilia infection. In immunocompetent rat lung infection models of S. maltophilia, humanized dosing of cefiderocol (2 g every 8 hours) and meropenem (1 g every 8 hours) revealed pharmacokinetic profiles similar to those in human subjects and the humanized cefiderocol dosing significantly reduced the lung viable bacteria cell count compared with baseline controls, which r eceived no intervention. Together, the results from these studies suggest that cefiderocol could provide an effective alternative treatment option for S. maltophilia infections in the lower respiratory tract, particularly strains resistant to empiric antibiotics, such as trimethoprim/sulfamethoxazole or minocycline. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Therapeutic cardiac arrest as an adjunct to resuscitative endovascular balloon occlusion of the aorta: Bridging the gap from fatal hemorrhage to definitive surgical control in swine

xloma.fota13 shared this article with you from Inoreader Therapeutic cardiac arrest as an adjunct to resuscitative endovascular balloon occlusion of the aorta: Bridging the gap from fatal hemorrhage to definitive surgical control in swine Via Journal of Trauma and Acute Care Surgery - Current Issue BACKGROUND Uncontrolled hemorrhage is the leading cause of potentially survivable combat casualty mortality, with 86.5% of cases resulting from noncompressible torso hemorrhage. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a minimally invasive technique used to stabilize patients with noncompressible torso hemorrhage; however, its application can take an average of 8 minutes to place. One therapeutic capable of bridging this gap is adenosine-lidocaine-magnesium (ALM), which at high doses induces a reversible cardioplegia. We hypothesize by using ALM as an adjunct to REBOA, the ALM-induced cardiac arrest will temporarily halt exsanguination and reduce blood loss, allowing for REBOA placement and control of bleeding. METHODS Male Yorkshire swine (60–80 kg) were randomly assigned to REBOA only or ALM-REBOA (n = 8/group). At baseline, uncontrolled hemorrhage was induced via a 1.5-cm right femoral arteriotomy, and hemorrhaged blood was quantified. One minute after injury (S1), ALM was administered, and 7 minutes later (T0), zone 1 REBOA inflation occurred. If cardiac arrest ensued, cardiac function either recovered spontaneously or advanced life support was initiated. At T30, surgical hemostasis was obtained, and REBOA was deflated. Animals were resuscitated until they were humanely euthanized at T90. RESULTS During field care phase, heart rate and end-tidal CO2 of the ALM-REBOA group were significantly lower than the REBOA only group. While mean arterial pressure significantly decreased from baseline, no significant differences between groups were observed throughout the field care phase. There was no significant difference in survival between the two groups (ALM-REBOA = 89% vs. REBOA only = 100%). Total blood loss was significantly decreased in the ALM-REBOA group (REBOA only = 24.32 ± 1.89 mL/kg vs. ALM-REBOA = 17.75 ± 2.04 mL/kg, p = 0.0499). CONCLUSION Adenosine-lidocaine-magnesium is a novel therapeutic, which, when used with REBOA, can significantly decrease the amount of blood loss at initial presentation, without compromising survival. This study provides proof of concept for ALM and its ability to bridge the gap between patient presentation and REBOA placement. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The swine as a vehicle for research in trauma-induced coagulopathy: Introducing principal component analysis for viscoelastic coagulation tests

xloma.fota13 shared this article with you from Inoreader The swine as a vehicle for research in trauma-induced coagulopathy: Introducing principal component analysis for viscoelastic coagulation tests Via Journal of Trauma and Acute Care Surgery - Current Issue BACKGROUND Uncontrolled bleeding is the leading cause of potentially preventable deaths among trauma patients. Tissue injury and shock result in trauma-induced coagulopathy (TIC). There are still uncertainties regarding detection methods and best practice management for TIC, and a deeper understanding of the pathophysiology requires robust animal models. The applicability of swine in coagulation studies, particularly after trauma has not been sufficiently elucidated. We, therefore, evaluated the swine as a vehicle for TIC research in a selection of trauma modalities. METHODS Twenty-six landrace swine (3 females/23 males) (mean weight, 60.0 kg) were anesthetized and randomized to negative controls, receiving no manipulation (n = 5), positive controls by hemodilution (n = 5), pulmonary contusion without hemorrhage (n = 5), pulmonary contusion with hemorrhage (n = 5), and blast polytrauma with hypothermia, hypoperfusion, hypoventilation, and systemic inflammation (n = 6). A comprehensive coagulation panel was analyzed at baseline, 20 minutes and 120 minutes after trauma. RESULTS PT(INR), aPTT, thrombocytes, and fibrinogen did not change after trauma. D-dimer increased (p View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Ethinyl estradiol sulfate acts without fluid resuscitation through estrogen receptors to rapidly protect the cardiovascular system from severe hemorrhage

xloma.fota13 shared this article with you from Inoreader Ethinyl estradiol sulfate acts without fluid resuscitation through estrogen receptors to rapidly protect the cardiovascular system from severe hemorrhage Via Journal of Trauma and Acute Care Surgery - Current Issue BACKGROUND Our in vivo rodent and pig model evidenced that estrogen and its derivative, ethinyl estradiol sulfate (EES), promote survival following hemorrhagic shock. To determine its mechanism, we first confirmed EES binding to estrogen receptor (ER) and improving/restoring cellular signaling, countering the assumption that EES, an ethinyl estradiol metabolite, is inactive. In addition, we examined if EES acts rapidly, consistent with nongenomic signaling. We selected the biomarkers of cardiovascular performance, reduction of apoptosis and proinflammatory responses, and elaboration of nitric oxide (NO) to validate efficacy. METHODS A rat trauma-hemorrhage model, consisting of a midline laparotomy and controlled bleeding (60% blood loss) without fluid resuscitation, was used. At 30 minutes after hemorrhage, heart performance was monitored, and Western blots were used to quantify biochemical analytes. The specificity of EES for ER was profiled with ER antagonists. Binding studies by Sekisui XenoTech (Kansas City, KS) determined an LD50 value for EES binding the rat ER. RESULTS The EES IC50 value was 1.52 × 10−8 Mol/L, consistent with pharmacologic efficacy. Ethinyl estradiol sulfate raised mean arterial pressure and ±derivative of pressure over time (dP/dT) significantly (but did not fully restore) within a 30-minute window. Levels of apoptosis and activation of NF-κB were dramatically reduced, as was elaboration of nitric oxide (NO) by inducible nitric oxide synthase. Phospho-endothelial nitric oxide synthase (eNOS) was restored to physiological levels. The restoration of cellular signaling occurs before restoration of cardiac contractility. CONCLUSION Ethinyl estradiol sulfate is a potent drug for improving heart performance, which also dramatically reduces damage by apoptosis, proinflammatory activity, and NO production, validating that EES can blunt multiple harmful outcomes arising from hypoxia and hypovolemia. The actions are dependent on receptor engagement, where specificity is confirmed by ER antagonists. The constraint of a 30-minute sampling window affirms that the responses are nongenomic and very likely restricted to cell-surface receptor engagement. The rapidity of these responses makes EES promising for intervention in the "golden hour." View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Administration of valproic acid in clinically approved dose improves neurologic recovery and decreases brain lesion size in swine subjected to hemorrhagic shock and traumatic brain injury

xloma.fota13 shared this article with you from Inoreader Administration of valproic acid in clinically approved dose improves neurologic recovery and decreases brain lesion size in swine subjected to hemorrhagic shock and traumatic brain injury Via Journal of Trauma and Acute Care Surgery - Current Issue BACKGROUND Traumatic brain injury (TBI) and hemorrhage remain the leading causes of death after trauma. We have previously shown that a dose of valproic acid (VPA) at (150 mg/kg) can decrease brain lesion size and hasten neurologic recovery. The current Food and Drug Administration–approved dose of VPA is 60 mg/kg. We evaluate neurologic outcomes and brain lesion size of a single dose of VPA at a level currently within Food and Drug Administration–approved dose in swine subjected to TBI and hemorrhagic shock. METHODS Swine (n = 5/group) were subjected to TBI and 40% blood volume hemorrhage. Animals remained in shock for 2 hours before randomization to normal saline (NS) resuscitation alone (control), NS-VPA 150 mg/kg (VPA 150), or NS-VPA 50 mg/kg (VPA 50). Neurologic severity scores (range, 0–32) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day (PID) 3. RESULTS Shock severity and laboratory values were similar in all groups. Valproic acid–treated animals demonstrated significantly less neurologic impairment on PID 1 and returned to baseline faster (PID 1 mean neurologic severity score, control = 22 ± 3 vs. VPA 150 mg/kg = 8 ± 7 or VPA 50 mg/kg = 6 ± 6; p = 0.02 and 0.003). Valproic acid–treated animals had significantly smaller brain lesion sizes (mean volume in mm3, control = 1,268.0 ± 241.2 vs. VPA 150 mg/kg = 620.4 ± 328.0 or VPA 50 mg/kg = 438.6 ± 234.8; p = 0.007 and 0.001). CONCLUSION In swine subjected to TBI and hemorrhagic shock, VPA treatment, in a dose that is approved for clinical use, decreases brain lesion size and reduces neurologic impairment compared with resuscitation alone. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.