Semi-mechanistic PK/PD modelling of fosfomycin and sulbactam combination against carbapenem-resistant Acinetobacter baumannii.

Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates.Synergism of FOS/SUL against 50 clinical CR-AB isolates were screened using the checkerboard method. Thereafter, time-kill studies against two CR-AB isolates were performed. The time-kill data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Monte Carlo simulations were then performed to estimate the probability of stasis, 1-log kill and 2-log kill after 24-hours with combination therapy.The FOS/SUL combination demonstrated a synergistic effect against 74% of isolates. No antagonism was observed. The MIC50 and MIC90 of FOS/SUL were decreased four- to eight-fold, compared to the monotherapy MIC50 and MIC90 In the time-kill studies, the combination displayed bactericidal activity against both isolates and synergistic activity against one isolate, at the highest clinically achievable concentrations. Our PK/PD model was able to describe the interaction between fosfomycin and sulbactam in vitro Bacterial kill was mainly driven by sulbactam, with fosfomycin augmentation. FOS/SUL regimens that included sulbactam 4 g every 8 hours, demonstrated a probability of target attainment of 1-log10 kill at 24 h of ∼69-76%, as compared to ∼15-30% with monotherapy regimens at the highest doses.The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that FOS/SUL may potentially be effective against some CR-AB infections.

Gut-derived serotonin contributes to bone deficits in colitis.

Osteoporosis and bone fractures occur at higher frequency in patients with inflammatory bowel disease (IBD), and decreased bone mass is observed in animal models of colitis. Another consistent feature of colitis is increased serotonin (5-HT) availability in the intestinal mucosa. Since gut-derived 5-HT can decrease bone mass, via activation of 5-HT1B receptors on pre-osteoblasts, we tested the hypothesis that 5-HT contributes to bone loss in colitis. Colitis was chronically induced in mice by adding dextran sodium sulfate (DSS) to their drinking water for 21 days. At day 21, circulating 5-HT levels were elevated in DSS-inflamed mice. Micro-computed tomography of femurs showed a decrease in trabecular bone volume fraction, formation, and surface area, due largely to decreased trabecular numbers in DSS-treated mice. The colitis-induced loss of trabecular bone was significantly suppressed in mice treated with the 5-HT synthesis inhibitor, p-chloro-DL-phenylalanine (PCPA; 300 mg/kg/day IP daily), and in mice treated with the 5-HT1B receptor antagonist GR55562 (1 mg/Kg/day SC daily). The 5-HT reuptake transporter (SERT) is critical for moving 5-HT from the interstitial space into enterocytes and from serum into platelets. Mice lacking SERT exhibited significant deficits in trabecular bone mass that are similar to those observed in DSS-inflamed mice, and these deficits were not extensively worsened by DSS-induced colitis in the SERT-/- mice. Taken together, findings from both the DSS and SERT-/- mouse models support a contributing role for 5-HT as a significant factor in bone loss induced by colitis.

Delivering precision antimicrobial therapy through closed-loop control systems.

Sub-optimal exposure to antimicrobial therapy is associated with poor patient outcomes and the development of antimicrobial resistance. Mechanisms for optimizing the concentration of a drug within the individual patient are under development. However, several barriers remain in realizing true individualization of therapy. These include problems with plasma drug sampling, availability of appropriate assays, and current mechanisms for dose adjustment. Biosensor technology offers a means of providing real-time monitoring of antimicrobials in a minimally invasive fashion. We report the potential for using microneedle biosensor technology as part of closed-loop control systems for the optimization of antimicrobial therapy in individual patients.

Comparative total and unbound pharmacokinetics of cefazolin administered by bolus versus continuous infusion in patients undergoing major surgery: a randomized controlled trial.

BACKGROUND.: Perioperative administration of cefazolin reduces the incidence of perioperative infections. Intraoperative re-dosing of cefazolin is commonly given between 2 and 5 h after the initial dose. This study was undertaken to determine whether intraoperative continuous infusions of cefazolin achieve better probability of target attainment (PTA) and fractional target attainment (FTA) than intermittent dosing. METHODS.: Patients undergoing major surgery received cefazolin 2 g before surgical incision. They were subsequently randomized to receive either an intermittent bolus (2 g every 4 h) or continuous infusion (500 mg h -1 ) of cefazolin until skin closure. Blood samples were analysed for total and unbound cefazolin concentrations using a validated chromatographic method. Population pharmacokinetic modelling was performed using Pmetrics ® software. Calculations of PTA and FTA were performed for common pathogens. RESULTS.: Ten patients were enrolled in each arm. A two-compartment linear model best described the time course of the total plasma cefazolin concentrations. The covariates that improved the model were body weight and creatinine clearance. Protein binding varied with time [mean (range) 69 (44-80)%] with a fixed 21% unbound value of cefazolin used for the simulations (120 min post-initial dosing). Mean ( sd ) central volume of distribution was 5.73 (2.42) litres, and total cefazolin clearance was 4.72 (1.1) litres h -1 . Continuous infusions of cefazolin consistently achieved better drug exposures and FTA for different weight and creatinine clearances, particularly for less susceptible pathogens. CONCLUSIONS.: Our study demonstrates that intraoperative continuous infusions of cefazolin increase the achievement of target plasma concentrations, even with lower infusion doses. Renal function and body weight are important when considering the need for alternative dosing regimens. CLINICAL TRIAL REGISTRATION.: NCT02058979.

The effect of pharmacists on ward rounds measured by the STOPP/START tool in a specialized geriatric unit.

WHAT IS KNOWN AND OBJECTIVE: The STOPP/START tool has been validated to assess elderly patients for potentially inappropriate prescribing. This study aimed to assess the effect of inclusion of a pharmacist on a physician-led ward round on potentially inappropriate prescribing in hospitalized elderly patients. METHODS: This was an observational study of prescribing for patients using the STOPP/START tool at three points during hospital stay; admission to hospital, on transfer to the specialized geriatric unit and on discharge from hospital. Data were collected over 4 months pre- and post-introduction of a pharmacist to a physician-led ward round. Demographic and clinical data, including total number of medications and STOPP/START criteria met, were collected. The mean number of STOPP/START criteria at each time-point was compared for pre- and post-introduction of a pharmacist using a Mann-Whitney U-test. The mean number of criteria for each time-point within each group was compared using a paired Student's t-test. RESULTS AND DISCUSSION: The demographic characteristics of the participants in the pre- and post-intervention groups were similar. The post-intervention group had numerically less STOPP/START criteria, mean 1·18 (1·37) compared to the pre-intervention group 1·50 (1·41), P = 0·07 at discharge. The pre-intervention group had no significant change in the criteria from admission 1·78 (1·57) to geriatric unit transfer 1·72 (1·54) (P = 0·37); however, there was a significant decrease from geriatric unit transfer 1·72 (1·54) to discharge 1·50 (1·41) (P = 0·02). The post-intervention group had a significant decrease from hospital admission 2·30 (1·91) to geriatric unit transfer 1·59 (1·60) (P < 0·01) and again to discharge 1·18 (1·37) (P < 0·01). WHAT IS NEW AND CONCLUSION: Pharmacist participation on the ward round in a specialized geriatric unit resulted in a numerical improvement in prescribing quality as measured by the STOPP/START tool.

Comparative Population Plasma and Tissue Pharmacokinetics of Micafungin in Critically Ill Patients with Severe Burn Injuries and Patients with Complicated Intra-Abdominal Infection.

Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of micafungin in the plasma and burn eschar of severely burned patients with those of micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 ± 0.47 versus 0.15 ± 0.06 h(-1), respectively; P < 0.05). Most patients would achieve plasma PK/pharmacodynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of ≤0.008 mg/liter and ≤0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively.

Population pharmacokinetics of linezolid in critically ill patients on renal replacement therapy: comparison of equal doses in continuous venovenous haemofiltration and continuous venovenous haemodiafiltration.

OBJECTIVES: Few data are available to guide linezolid dosing during renal replacement therapy. The objective of this study was to compare the population pharmacokinetics of linezolid during continuous venovenous haemofiltration (CVVHF, 30 mL/kg/h) and continuous venovenous haemodiafiltration (CVVHDF, 15 mL/kg/h + 15 mL/kg/h). METHODS: Patients requiring linezolid 600 mg iv every 12 h and CVVHF or CVVHDF were eligible for this prospective study. Seven blood samples were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis was undertaken using Pmetrics. Monte Carlo simulations evaluated achievement of a pharmacodynamics target of an AUC from 0-24 h to MIC (AUC0-24/MIC) of 80. RESULTS: Nine CVVHDF and eight CVVHF treatments were performed in 13 patients. Regimens of CVVHDF and CVVHF were similar. A two-compartment linear model best described the data. CVVHDF was associated with a 20.5% higher mean linezolid clearance than CVVHF, without statistical significance (P = 0.39). Increasing patient weight and decreasing SOFA score were associated with increasing linezolid clearance. The mean (SD) parameter estimates were: clearance (CL), 3.8 (2.2) L/h; volume of the central compartment, 26.5 (10.3) L; intercompartmental clearance constants from central to peripheral, 8.1 (12.1) L/h; and peripheral to central compartments, 3.6 (4.0) L/h. Achievement of pharmacodynamic targets was poor for an MIC of 2 mg/L with the studied dose. CONCLUSIONS: During CVVHF and CVVHDF, there is profound pharmacokinetic variability of linezolid. Suboptimal achievement of therapeutic targets occurs at the EUCAST breakpoint MIC of 2 mg/L using 600 mg iv every 12 h.

Integrated pharmacokinetic-pharmacodynamic modelling to evaluate antimicrobial prophylaxis in abdominal surgery.

OBJECTIVES: To use Monte Carlo simulation with an integrated pharmacokinetic-pharmacodynamic (PK-PD) model to evaluate guideline-recommended antimicrobial prophylaxis (AP) regimens with anaerobic coverage in abdominal surgery. METHODS: AP regimens were tested in simulated subjects undergoing elective abdominal surgery using relevant PK models and pathogen distributions in surgical site infections (SSIs). Predicted cumulative target attainment was the percentage of simulated subjects with free (unbound) antimicrobial plasma concentrations above the MICs for potential SSI pathogens. RESULTS: Cefazolin plus metronidazole covered SSI aerobes in 70% and the Bacteroides fragilis group in 99% of subjects, whereas cefoxitin only covered aerobes and anaerobes in 63% and 27% of cases, respectively. The broad-spectrum ceftriaxone plus metronidazole covered aerobes in 82% and anaerobes in 99% of simulations, while ertapenem covered aerobes in 88% and anaerobes in 90% of cases. Clindamycin covered the B. fragilis group in only 11% of cases. For cefazolin, 2 g doses maintained target attainment in simulated subjects from 80 to 120 kg, whereas 1 g doses were associated with lower target attainment against potential Gram-negative pathogens even in those <80 kg. For gentamicin, 3 mg/kg doses were comparable to the suggested 5 mg/kg, but superior to the traditional 1.5 mg/kg. CONCLUSIONS: This study demonstrates the use of PK-PD to inform decisions regarding AP in abdominal surgery. In this case, the findings support avoiding cefoxitin, avoiding clindamycin for anaerobic coverage, selecting 2 g doses of cefazolin even in patients <80 kg and using 3 mg/kg doses of gentamicin.

Tigecycline use in the outpatient parenteral antibiotic therapy setting.

In the context of globally increasing antimicrobial resistance, tigecycline appears to be a useful therapeutic option. The need for prolonged courses for complex infections has prompted consideration of its use via outpatient parenteral antibiotic therapy (OPAT) programmes, although clinical outcomes when used in this setting remain unknown. We retrospectively reviewed the patient characteristics and outcomes of 11 patients who received tigecycline, most commonly delivered as 100 mg once daily, via OPAT at three tertiary Australian hospitals. Rates of co-morbidity and prior antibiotic use were high. Patients had a wide range of infections including bone and/or joint (n = 5), intra-abdominal (n = 3), lower respiratory tract (n = 2) and parapharyngeal abscess (n = 1). Mycobacterial species (n = 5) were the most frequent pathogen, and multi-resistant organisms were common (n = 4). The median OPAT duration was 14 days (IQR 6-30). Nausea was encountered in 45 % of cases. At completion of OPAT, 1 patient (9 %) was cured, 2 (18 %) had improved and 8 (73 %) failed therapy. Failure occurred due to either progression or non-response of infection (n = 4), re-admission (n = 3), premature cessation of tigecycline due to nausea (n = 3) or death (n = 1). Whilst OPAT delivery of tigecycline is a therapeutic option, when used as second-line therapy for complex, often multi-resistant infections in patients with multiple comorbidities, high rates of clinical failure, readmissions and adverse effects, especially nausea, should be anticipated.

Plasma and peritoneal fluid population pharmacokinetics of micafungin in post-surgical patients with severe peritonitis.

OBJECTIVES: Limited information about the pharmacokinetics of micafungin in the peritoneal cavity is available. The aim of this study was to explore the pharmacokinetics/pharmacodynamics of micafungin in plasma and peritoneal fluid in post-surgical critically ill patients with proven or suspected intra-abdominal fungal infection. METHODS: Patients were administered 100 mg/day micafungin. Serial blood and peritoneal fluid samples were collected on day 1 and day 3 (steady-state) of treatment. Concentrations were determined by validated chromatography and were subject to a population pharmacokinetic analysis with Pmetrics(®). Monte Carlo simulations were performed for AUC0-24/MIC ratios in plasma. The PTA was calculated using AUC0-24/MIC cut-offs: 285 for Candida parapsilosis and 3000 for non-parapsilosis Candida spp. RESULTS: Ten patients were included; six were male. The median (range) age, APACHE II score and Mannheim peritonitis index were 72 (43-85) years, 15 (11-36) and 26 (8-37), respectively. On day 1, median (SD) penetration of micafungin into the peritoneal cavity was 30% (30%-40%). A three-compartment model adequately described the data. The mean (SD) estimates for clearance and volume of distribution of the central compartment were 1.27 (0.75) L/h and 9.26 (1.11) L, respectively. In most patients, the PTA in plasma was ≥ 90% for MICs of 0.008-0.016 mg/L for Candida spp. and 0.125-0.25 mg/L for C. parapsilosis. CONCLUSIONS: After the first dose, micafungin at 100 mg/day achieves pharmacokinetic/pharmacodynamic targets in plasma for Candida spp. and C. parapsilosis MICs of 0.008-0.016 and 0.125-0.25 mg/L, respectively.

Antibiotic dose optimization in critically ill patients.

The judicious use of existing antibiotics is essential for preserving their activity against infections. In the era of multi-drug resistance, this is of particular importance in clinical areas characterized by high antibiotic use, such as the ICU. Antibiotic dose optimization in critically ill patients requires sound knowledge not only of the altered physiology in serious infections - including severe sepsis, septic shock and ventilator-associated pneumonia - but also of the pathogen-drug exposure relationship (i.e. pharmacokinetic/pharmacodynamic index). An important consideration is the fact that extreme shifts in organ function, such as those seen in hyperdynamic patients or those with multiple organ dysfunction syndrome, can have an impact upon drug exposure, and constant vigilance is required when reviewing antibiotic dosing regimens in the critically ill. The use of continuous renal replacement therapy and extracorporeal membrane oxygenation remain important interventions in these patients; however, both of these treatments can have a profound effect on antibiotic exposure. We suggest placing emphasis on the use of therapeutic drug monitoring and dose individualization when optimizing therapy in these settings.

Individualization of piperacillin dosing for critically ill patients: dosing software to optimize antimicrobial therapy.

Piperacillin-tazobactam is frequently used for empirical and targeted therapy of infections in critically ill patients. Considerable pharmacokinetic (PK) variability is observed in critically ill patients. By estimating an individual's PK, dosage optimization Bayesian estimation techniques can be used to calculate the appropriate piperacillin regimen to achieve desired drug exposure targets. The aim of this study was to establish a population PK model for piperacillin in critically ill patients and then analyze the performance of the model in the dose optimization software program BestDose. Linear, with estimated creatinine clearance and weight as covariates, Michaelis-Menten (MM) and parallel linear/MM structural models were fitted to the data from 146 critically ill patients with nosocomial infection. Piperacillin concentrations measured in the first dosing interval, from each of 8 additional individuals, combined with the population model were embedded into the dose optimization software. The impact of the number of observations was assessed. Precision was assessed by (i) the predicted piperacillin dosage and by (ii) linear regression of the observed-versus-predicted piperacillin concentrations from the second 24 h of treatment. We found that a linear clearance model with creatinine clearance and weight as covariates for drug clearance and volume of distribution, respectively, best described the observed data. When there were at least two observed piperacillin concentrations, the dose optimization software predicted a mean piperacillin dosage of 4.02 g in the 8 patients administered piperacillin doses of 4.00 g. Linear regression of the observed-versus-predicted piperacillin concentrations for 8 individuals after 24 h of piperacillin dosing demonstrated an r(2) of >0.89. In conclusion, for most critically ill patients, individualized piperacillin regimens delivering a target serum piperacillin concentration is achievable. Further validation of the dosage optimization software in a clinical trial is required.

Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014.

Antifungal agents may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy. These risks may be minimised by clinical assessment, laboratory monitoring, avoidance of particular drug combinations and dose modification. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre-hydration and electrolyte supplementation may also be required. Therapeutic drug monitoring (TDM) of antifungal agents is warranted, especially where non-compliance, non-linear pharmacokinetics, inadequate absorption, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Recommended indications for voriconazole and posaconazole TDM in the clinical management of haematology patients are provided. With emerging knowledge regarding the impact of pharmacogenomics upon metabolism of azole agents (particularly voriconazole), potential applications of pharmacogenomic evaluation to clinical practice are proposed.

First Report of Xanthomonas translucens Causing Etiolation on Creeping Bentgrass Turf in Illinois, Kentucky, and North Carolina.

Symptoms of etiolation, which is an abnormal elongation and yellowing of tillers, have been observed on creeping bentgrass [Agrostis stolonifera L. (CBG)] putting greens for decades; however, symptoms are typically transient and non-problematic. Reports of etiolation have become more frequent recently and research supports the involvement of bacteria (1). During stressful summer periods in 2011 and 2012, 62 CBG putting green samples were submitted to the NCSU Turf Clinic exhibiting symptoms of etiolation, chlorosis, and/or general decline. Microscopic examination of stem and leaf tissue often showed bacterial streaming from the xylem tissue. Symptomatic tissue was surface disinfested in sodium hypochlorite (10% Clorox) for 5 min, blotted dry, and rinsed in sterile dH2O. Disinfested tissue was placed in a small drop of sterile dH2O on a glass microscope slide and cut to allow bacteria to stream into the water for 2 min. The resulting bacterial suspension was streaked onto three nutrient agar (NA) plates and incubated at 30°C overnight. Bacterial colonies varied in morphology and those present in the greatest number based on morphology were re-streaked to isolate individual colonies. Bacterial isolates were tentatively identified to species using rDNA sequencing of 16S and ITS regions (3). Sequencing results showed isolates obtained from 6 locations (in Illinois, Kentucky, and North Carolina) having a positive match (≥99% 16S and ≥93% ITS) to Xanthomonas translucens (GenBank accessions AY572961, HM181927, JX976312, AY253329, and AB680445). Additional research is needed to confirm pathovar designation as X. translucens isolates were similar to both poae and graminis pathovars. A representative isolate (LW10-12A) was also examined for carbon source utilization using the BIOLOG 3rd Gen Microplate (Biolog Inc., Hayward, CA) resulting in a positive identification of X. translucens. Isolate LW10-12A was used to inoculate 6-week-old seeded creeping bentgrass cv. A1 plants maintained at 1 cm height in 3.5 cm diameter containers. Scissors were dipped in a cell suspension (~109 CFU ml-1 in sterile dH2O) and used to cut healthy CBG plants at 1 cm height and the remaining suspension was applied to the foliage until runoff using an atomizer bottle. Non-inoculated plants were cut and misted using sterile dH2O. After inoculation, plants were placed in a sealed clear plastic Camwear container (Cambro Co., Huntington Beach, CA) for 48 h and then transferred to the growth chamber bench (30°C) receiving irrigation twice daily with dH2O. Etiolation was rated within each of the four replicates by counting the number of etiolated leaves that were easily observed as significantly higher than the rest of the turf canopy. Plants inoculated with X. translucens exhibited etiolation of the youngest leaf within 48 h, whereas the non-inoculated plants did not. Symptoms were similar to observations in the field, as etiolated leaves were chlorotic and easily extracted from the turf surface. Microscopic examination showed bacterial streaming and identification of bacteria, using the previously described methods, was positive for X. translucens. Etiolation symptoms persisted over multiple weeks, but a decline in turf quality was not observed. Etiolation has been previously suggested as a precursor to bacterial wilt, caused by X. translucens pv. poae, on annual bluegrass [Poa annua L. f. reptans (Hausskn) T. Koyama] (2) and Acidovorax avenae has also been shown to produce etiolation on CBG (1). To our knowledge, this is the first confirmation of X. translucens as a cause of etiolation in CBG. References: (1) P. R. Giordano et al. Plant Dis. 96:1736, 2012. (2) N. A. Mitkowski et al. Plant Dis. 89:469, 2005. (3) N. W. Schaad et al. Lab. Guide for Ident. of Plant Path Bac., 2001.

Outpatient parenteral antimicrobial therapy with carbapenems: A systematic review.

OBJECTIVE: To review the literature on parenteral carbapenems in OPAT and present comprehensive evidence on their safety, efficacy, and stability. METHODS: A systematic review following PRISMA guidelines was conducted through 17 January 2024, using PubMed, Embase, Web of Science, Scopus, and the Cochrane Library to find relevant articles. RESULTS: Ertapenem (1 g QD) in OPAT showed high clinical (81-97%) and microbiological (67-90.9%) success rates. Ertapenem (1 g QD) was also comparable to piperacillin/tazobactam (3.375 g every 6 h) for complicated skin infections and superior to cefazolin (2 g every 8 h) and oxacillin (2 g every 4-6 h) for various infections. Ertapenem monotherapy, once daily, achieved an 81% clinical cure rate for urinary tract infections. Additionally, subcutaneous ertapenem in OPAT showed outcomes comparable to parenteral routes. Meropenem continuous infusion (CI) may also be considered safe and effective in selected patient populations; however, its use in OPAT as a CI is limited due to stability concerns. CONCLUSION: Parenteral carbapenems are effective, and well-tolerated OPAT treatment options; nonetheless, further studies are warranted to optimize the stability and/or dosing regimens of meropenem and enable its wider use.

The pharmacokinetics of ganciclovir during prolonged intermittent kidney replacement therapy in a cardiac transplant recipient.

Ganciclovir, a guanine analogue, is used intravenously (IV) first-line for the prophylaxis and treatment of cytomegalovirus (CMV) infection in solid organ transplant recipients. The pharmacokinetics (PK) of ganciclovir are highly variable, with myelosuppression occurring at high concentrations. Ganciclovir is primarily renally excreted as the parent compound, and clearance is significantly reduced in renal impairment. Acute kidney injury (AKI) is a common post-operative complication of cardiac transplantation, reducing the clearance of ganciclovir. In the intensive care unit (ICU), AKI is often managed by kidney replacement therapy (KRT). One form of KRT, prolonged intermittent kidney replacement therapy (PIKRT) is increasingly used for cost and flexibility advantages. Ganciclovir dosing recommendations are available for varying degrees of renal impairment and KRT, except for PIKRT. In this case of cardiac transplantation, complicated by anuric AKI, a ganciclovir dose of 2.0-2.5 mg/kg of adjusted body weight given after each PIKRT session was demonstrated to achieve PK targets.

Quantitative theory of driven nonlinear brain dynamics.

Strong periodic stimuli such as bright flashing lights evoke nonlinear responses in the brain and interact nonlinearly with ongoing cortical activity, but the underlying mechanisms for these phenomena are poorly understood at present. The dominant features of these experimentally observed dynamics are reproduced by the dynamics of a quantitative neural field model subject to periodic drive. Model power spectra over a range of drive frequencies show agreement with multiple features of experimental measurements, exhibiting nonlinear effects including entrainment over a range of frequencies around the natural alpha frequency f(α), subharmonic entrainment near 2f(α), and harmonic generation. Further analysis of the driven dynamics as a function of the drive parameters reveals rich nonlinear dynamics that is predicted to be observable in future experiments at high drive amplitude, including period doubling, bistable phase-locking, hysteresis, wave mixing, and chaos indicated by positive Lyapunov exponents. Moreover, photosensitive seizures are predicted for physiologically realistic model parameters yielding bistability between healthy and seizure dynamics. These results demonstrate the applicability of neural field models to the new regime of periodically driven nonlinear dynamics, enabling interpretation of experimental data in terms of specific generating mechanisms and providing new tests of the theory.

The potential for underutilized crops to improve security of food production.

Staple crops face major challenges in the near future and a diversification away from over-reliance on staples will be important as part of the progress towards the goal of achieving security of food production. Underutilized or neglected crops species are often indigenous ancient crop species which are still used at some level within the local, national or even international communities, but have the potential to contribute further to the mix of food sources than they currently do. The most cost-effective and easily disseminated changes that can be made to a crop are changes to the genetics, as these are contained within the seed itself and, for many species, the seed is a pure breeding, self-replicating, resource. This article focuses on the potential of underutilized crops to contribute to food security and, in particular, whether genetics and breeding can overcome some of the constraints to the enhanced uptake of these species in the future. The focus here is on overview rather than detail and subsequent articles will examine the current evidence base.

Physiological implications of genomic state in parthenogenetic lizards of reciprocal hybrid origin.

Parthenogenesis often evolves in association with hybridization, but the associated ecological consequences are poorly understood. The Australian gecko Heteronotia binoei is unusual because triploid parthenogenesis evolved through reciprocal crosses between two sexual lineages, resulting in four possible cytonuclear genotypes. In this species complex, we compared the performance of these parthenogenetic genotypes with their sexual progenitors for a suite of physiological traits (metabolic rate, thermal tolerance, locomotor performance, and in vitro activity and gene sequence divergence of a cytonuclear metabolic pathway, cytochrome C oxidase). Mass-specific metabolic rate scaled differently with body mass for parthenogens and sexuals, while heat tolerance provided the only evidence for cytonuclear incompatibility in hybrid parthenogens. The most prominent phenotypic effects were attributable to nuclear genome dosage. Overall, our results suggest that the hybrid/polyploidy origin of parthenogenetic H. binoei has had surprisingly few negative fitness consequences and may have produced a broader overall niche for the species.

Pharmacodynamics of ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus: is it a viable treatment option?

Ceftriaxone is a broad-spectrum cephalosporin that may be one option to treat methicillin-susceptible Staphylococcus aureus (MSSA). Although MSSA may be susceptible to ceftriaxone, the minimum inhibitory concentration (MIC) is generally two- to four-fold higher than other susceptible bacterial pathogens. This study aimed to explore the pharmacodynamics of ceftriaxone against MSSA and to determine the likely optimal dose. A hollow-fibre infection model was used with one clinical MSSA isolate (MIC = 4 mg/L) at an initial inoculum of 1 × 106 CFU/mL. Ceftriaxone dosing regimens of 1 g once and twice daily and 2 g once and twice daily were simulated. Ceftriaxone 1 g dosing regimens did not substantially impact bacterial killing within the first 12 h. Conversely, when administered as a 2 g dose either once or twice daily, an approximate 1-log10 bacterial reduction was observed where it plateaued for up to 96 h. No resistance was identified. Only a high ceftriaxone dose of 2 g twice daily achieves bacterial killing and sustained inhibition of bacterial growth. Ceftriaxone at routinely used doses is unsuitable for the treatment of MSSA infections and alternative agents should be preferentially used.