A ketogenic diet enhances fluconazole efficacy in murine models of systemic fungal infection.

Invasive fungal infections are a significant public health concern, with mortality rates ranging from 20% to 85% despite current treatments. Therefore, we examined whether a ketogenic diet could serve as a successful treatment intervention in murine models of Cryptococcus neoformans and Candida albicans infection in combination with fluconazole-a low-cost, readily available antifungal therapy. The ketogenic diet is a high-fat, low-carbohydrate diet that promotes fatty acid oxidation as an alternative to glycolysis through the production of ketone bodies. In this series of experiments, mice fed a ketogenic diet prior to infection with C. neoformans and treated with fluconazole had a significant decrease in fungal burden in both the brain (mean 2.66 ± 0.289 log10 reduction) and lung (mean 1.72 ± 0.399 log10 reduction) compared to fluconazole treatment on a conventional diet. During C. albicans infection, kidney fungal burden of mice in the keto-fluconazole combination group was significantly decreased compared to fluconazole alone (2.37 ± 0.770 log10-reduction). Along with higher concentrations of fluconazole in the plasma and brain tissue, fluconazole efficacy was maximized at a significantly lower concentration on a keto diet compared to a conventional diet, indicating a dramatic effect on fluconazole pharmacodynamics. Our findings indicate that a ketogenic diet potentiates the effect of fluconazole at multiple body sites during both C. neoformans and C. albicans infection and could have practical and promising treatment implications.IMPORTANCEInvasive fungal infections cause over 2.5 million deaths per year around the world. Treatments for fungal infections are limited, and there is a significant need to develop strategies to enhance antifungal efficacy, combat antifungal resistance, and mitigate treatment side effects. We determined that a high-fat, low-carbohydrate ketogenic diet significantly potentiated the therapeutic effect of fluconazole, which resulted in a substantial decrease in tissue fungal burden of both C. neoformans and C. albicans in experimental animal models. We believe this work is the first of its kind to demonstrate that diet can dramatically influence the treatment of fungal infections. These results highlight a novel strategy of antifungal drug enhancement and emphasize the need for future investigation into dietary effects on antifungal drug activity.

Advances in Hernia Care State of the Art.

The field of hernia surgery has seen many recent advances and continues to evolve. Care of the hernia patient begins preoperatively by ensuring adequate preparation for surgery with surgeons now having the opportunity to accurately predict risk which can aid with informed consent. Imaging studies can now help surgeons diagnose and plan hernia surgery on an individual level based on hernia characteristics as well as abdominal wall musculature. In the operating room, new technology and surgical techniques have allowed surgeons to become increasingly sophisticated with goals of reducing tension on midline closures, utilizing minimally invasive and robotic techniques, and availability of new and varied mesh prosthetics. While modest improvements in outcomes have been witnessed by these advances, there is still opportunity for improvement which will be realized by continued research, use of registries, and education and training. Hernia prevention strategies focusing on minimally invasive surgery, laparotomy closure, and the use of prophylactic mesh will also help with the burden of incisional hernias. These advances in hernia surgery have led to the new field of Abdominal Core Health which helps represent this evolving and growing new subspecialty of general surgery.

Determination of minimum inhibitory concentrations using machine-learning-assisted agar dilution.

Effective policy to address the global threat of antimicrobial resistance requires robust antimicrobial susceptibility data. Traditional methods for measuring minimum inhibitory concentration (MIC) are resource intensive, subject to human error, and require considerable infrastructure. AIgarMIC streamlines and standardizes MIC measurement and is especially valuable for large-scale surveillance activities. MICs were measured using agar dilution for n = 10 antibiotics against clinical Enterobacterales isolates (n = 1,086) obtained from a large tertiary hospital microbiology laboratory. Escherichia coli (n = 827, 76%) was the most common organism. Photographs of agar plates were divided into smaller images covering one inoculation site. A labeled data set of colony images was created and used to train a convolutional neural network to classify images based on whether a bacterial colony was present (first-step model). If growth was present, a second-step model determined whether colony morphology suggested antimicrobial growth inhibition. The ability of the AI to determine MIC was then compared with standard visual determination. The first-step model classified bacterial growth as present/absent with 94.3% accuracy. The second-step model classified colonies as "inhibited" or "good growth" with 88.6% accuracy. For the determination of MIC, the rate of essential agreement was 98.9% (644/651), with a bias of -7.8%, compared with manual annotation. AIgarMIC uses artificial intelligence to automate endpoint assessments for agar dilution and potentially increases throughput without bespoke equipment. AIgarMIC reduces laboratory barriers to generating high-quality MIC data that can be used for large-scale surveillance programs. IMPORTANCE: This research uses modern artificial intelligence and machine-learning approaches to standardize and automate the interpretation of agar dilution minimum inhibitory concentration testing. Artificial intelligence is currently of significant topical interest to researchers and clinicians. In our manuscript, we demonstrate a use-case in the microbiology laboratory and present validation data for the model's performance against manual interpretation.

Challenges for global antibiotic regimen planning and establishing antimicrobial resistance targets: implications for the WHO Essential Medicines List and AWaRe antibiotic book dosing.

SUMMARYThe World Health Organisation's 2022 AWaRe Book provides guidance for the use of 39 antibiotics to treat 35 infections in primary healthcare and hospital facilities. We review the evidence underpinning suggested dosing regimens. Few (n = 18) population pharmacokinetic studies exist for key oral AWaRe antibiotics, largely conducted in homogenous and unrepresentative populations hindering robust estimates of drug exposures. Databases of minimum inhibitory concentration distributions are limited, especially for community pathogen-antibiotic combinations. Minimum inhibitory concentration data sources are not routinely reported and lack regional diversity and community representation. Of studies defining a pharmacodynamic target for ß-lactams (n = 80), 42 (52.5%) differed from traditionally accepted 30%-50% time above minimum inhibitory concentration targets. Heterogeneity in model systems and pharmacodynamic endpoints is common, and models generally use intravenous ß-lactams. One-size-fits-all pharmacodynamic targets are used for regimen planning despite complexity in drug-pathogen-disease combinations. We present solutions to enable the development of global evidence-based antibiotic dosing guidance that provides adequate treatment in the context of the increasing prevalence of antimicrobial resistance and, moreover, minimizes the emergence of resistance.

Molecular pharmacodynamics of meropenem for nosocomial pneumonia caused by Pseudomonas aeruginosa.

Hospital-acquired pneumonia (HAP) is a leading cause of morbidity and mortality, commonly caused by Pseudomonas aeruginosa. Meropenem is a commonly used therapeutic agent, although emergent resistance occurs during treatment. We used a rabbit HAP infection model to assess the bacterial kill and resistance pharmacodynamics of meropenem. Meropenem 5 mg/kg administered subcutaneously (s.c.) q8h (±amikacin 3.33-5 mg/kg q8h administered intravenously[i.v.]) or meropenem 30 mg/kg s.c. q8h regimens were assessed in a rabbit lung infection model infected with P. aeruginosa, with bacterial quantification and phenotypic/genotypic characterization of emergent resistant isolates. The pharmacokinetic/pharmacodynamic output was fitted to a mathematical model, and human-like regimens were simulated to predict outcomes in a clinical context. Increasing meropenem monotherapy demonstrated a dose-response effect to bacterial kill and an inverted U relationship with emergent resistance. The addition of amikacin to meropenem suppressed the emergence of resistance. A network of porin loss, efflux upregulation, and increased expression of AmpC was identified as the mechanism of this emergent resistance. A bridging simulation using human pharmacokinetics identified meropenem 2 g i.v. q8h as the licensed clinical regimen most likely to suppress resistance. We demonstrate an innovative experimental platform to phenotypically and genotypically characterize bacterial emergent resistance pharmacodynamics in HAP. For meropenem, we have demonstrated the risk of resistance emergence during therapy and identified two mitigating strategies: (i) regimen intensification and (ii) use of combination therapy. This platform will allow pre-clinical assessment of emergent resistance risk during treatment of HAP for other antimicrobials, to allow construction of clinical regimens that mitigate this risk.IMPORTANCEThe emergence of antimicrobial resistance (AMR) during antimicrobial treatment for hospital-acquired pneumonia (HAP) is a well-documented problem (particularly in pneumonia caused by Pseudomonas aeruginosa) that contributes to the wider global antimicrobial resistance crisis. During drug development, regimens are typically determined by their sufficiency to achieve bactericidal effect. Prevention of the emergence of resistance pharmacodynamics is usually not characterized or used to determine the regimen. The innovative experimental platform described here allows characterization of the emergence of AMR during the treatment of HAP and the development of strategies to mitigate this. We have demonstrated this specifically for meropenem-a broad-spectrum antibiotic commonly used to treat HAP. We have characterized the antimicrobial resistance pharmacodynamics of meropenem when used to treat HAP, caused by initially meropenem-susceptible P. aeruginosa, phenotypically and genotypically. We have also shown that intensifying the regimen and using combination therapy are both strategies that can both treat HAP and suppress the emergence of resistance.

Forecasting The Impact of the 2023 Current Procedural Terminology Coding Changes On Ventral Hernia Work Relative Value Units. A Cross-Sectional Study.

BACKGROUND: In January 2023, significant changes were implemented to ventral hernia repair Current Procedural Terminology codes, with new codes replacing previous codes. The new codes were assigned a 0-day global period. The impact of these changes on clinical productivity remains unclear. Our objective was to forecast the impact of Current Procedural Terminology changes on ventral hernia-related work relative value units using historical data. METHODS: Ventral hernia repairs performed between March 2021 and December 2022 on adults by a single surgeon with available 90-day follow-up were retrospectively retrieved from the Abdominal Core Health Quality Collaborative. Demographic, hernia, and operative and postoperative data were collected. The ventral hernia repairs were coded twice using the previous and new Current Procedural Terminology codes, and work relative value units were calculated using both systems. The median work relative value units per case were compared using the Wilcoxon signed-rank test. RESULTS: A total of 143 ventral hernia repairs were included. The median age was 59 years, and 50% of patients were male. Median hernia width and length were 3.5 and 5.0 cm, respectively. The most common ventral hernia types were incisional 57% and umbilical 33%. Twenty percent of hernias were recurrent, and 99% were elective repairs. 49% of the procedures were open, 30% robotic, and 21% laparoscopic. Component separation was performed in 16%. The median length of stay was 0.0, and the median number of 90-day outpatient postoperative visits was 1.0. The new Current Procedural Terminology coding system was associated with a higher median 90-day work relative value units per case (14.1) than the previous system (13.8) (P = .002). Subset analysis identified statistically higher median 90-day work relative value units per case using the new versus previous Current Procedural Terminology codes for hernias with the largest defect dimension >10 cm (23.3 vs 18.8), umbilical/epigastric/Spigelian hernias (9.2 vs 7.1), recurrent hernias (20.1 vs 17.3) and open ventral hernia repairs (9.8 vs 7.1), all P < .05. Median 90-day work relative value units per case were statistically lower using the new versus previous codes for non-recurrent (11.6 vs 13.8) and incarcerated/strangulated (14.8 vs 14.9) hernias, all P < .05. In the new coding system, postoperative care within 90-days contributed to a median of 1.3 work relative value units per case (9% of total 90-day work relative value units). CONCLUSION: We forecast that in our practice, the 2023 ventral hernia repair Current Procedural Terminology changes will result in a modest impact on clinical productivity. The impact of these changes on a particular practice depends on surgical practice patterns and ventral hernia case mix.

Antimicrobial treatment imprecision: an outcome-based model to close the data-to-action loop.

Health-care systems, food supply chains, and society in general are threatened by the inexorable rise of antimicrobial resistance. This threat is driven by many factors, one of which is inappropriate antimicrobial treatment. The ability of policy makers and leaders in health care, public health, regulatory agencies, and research and development to deliver frameworks for appropriate, sustainable antimicrobial treatment is hampered by a scarcity of tangible outcome-based measures of the damage it causes. In this Personal View, a mathematically grounded, outcome-based measure of antimicrobial treatment appropriateness, called imprecision, is proposed. We outline a framework for policy makers and health-care leaders to use this metric to deliver more effective antimicrobial stewardship interventions to future patient pathways. This will be achieved using learning antimicrobial systems built on public and practitioner engagement; solid implementation science; advances in artificial intelligence; and changes to regulation, research, and development. The outcomes of this framework would be more ecologically and organisationally sustainable patterns of antimicrobial development, regulation, and prescribing. We discuss practical, ethical, and regulatory considerations involved in the delivery of novel antimicrobial drug development, and policy and patient pathways built on artificial intelligence-augmented measures of antimicrobial treatment imprecision.

Development and application of neonatal physiology-based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment.

Antimicrobial resistance increasingly complicates neonatal sepsis in a global context. Fosfomycin and amikacin are two agents being tested in an ongoing multicenter neonatal sepsis trial. Although neonatal pharmacokinetics (PKs) have been described for these drugs, the physiological variability within neonatal populations makes population PKs in this group uncertain. Physiologically-based pharmacokinetic (PBPK) models were developed in Simcyp for fosfomycin and amikacin sequentially for adult, pediatric, and neonatal populations, with visual and quantitative validation compared to observed data at each stage. Simulations were performed using the final validated neonatal models to determine drug exposures for each drug across a demographic range, with probability of target attainment (PTA) assessments. Successfully validated neonatal PBPK models were developed for both fosfomycin and amikacin. PTA analysis demonstrated high probability of target attainment for amikacin 15 mg/kg i.v. q24h and fosfomycin 100 mg/kg (in neonates aged 0-7 days) or 150 mg/kg (in neonates aged 7-28 days) i.v. q12h for Enterobacterales with fosfomycin and amikacin minimum inhibitory concentrations at the adult breakpoints. Repeat analysis in premature populations demonstrated the same result. PTA analysis for a proposed combination fosfomycin-amikacin target was also performed. The simulated regimens, tested in a neonatal sepsis trial, are likely to be adequate for neonates across different postnatal ages and gestational age. This work demonstrates a template for determining target attainment for antimicrobials (alone or in combination) in special populations without sufficient available PK data to otherwise assess with traditional pharmacometric methods.

Antimicrobial learning systems: an implementation blueprint for artificial intelligence to tackle antimicrobial resistance.

The proliferation of various forms of artificial intelligence (AI) brings many opportunities to improve health care. AI models can harness complex evolving data, inform and augment human actions, and learn from health outcomes such as morbidity and mortality. The global public health challenge of antimicrobial resistance (AMR) needs large-scale optimisation of antimicrobial use and wider infection care, which could be enabled by carefully constructed AI models. As AI models become increasingly useful and robust, health-care systems remain challenging places for their deployment. An implementation gap exists between the promise of AI models and their use in patient and population care. Here, we outline an adaptive implementation and maintenance framework for AI models to improve antimicrobial use and infection care as a learning system. The roles of AMR problem identification, law and regulation, organisational support, data processing, and AI development, assessment, maintenance, and scalability in the implementation of AMR-targeted AI models are considered.

Polymer versus Titanium Clips in Laparoscopic Cholecystectomy.

BACKGROUND: Surgical clips are commonly used during laparoscopic cholecystectomy for cystic duct and artery ligation. Titanium and polymer clips are the two most common types used for this indication. Given the cost-saving potential, design advantages, and decreased incidence of complications associated with polymer clips, we sought to study whether there is a clinically significant difference in outcome between polymer and titanium clips in laparoscopic cholecystectomy. METHODS: Fifty consecutive cases using polymer clips followed by 50 consecutive cases using metal clips over a 6-month period by residents under the direction of a single surgeon were retrospectively reviewed. The following outcomes were evaluated: incidence of bile leak, postoperative bleeding, need for additional procedures, hospital length of stay, and cost. RESULTS: We found that significantly more misfires occurred with the use of the polymer clips (n=17) than with the titanium clips (n=2, p<.001). Eight cases (16%) required opening of an additional polymer clip cartridge to complete the operation. Despite this additional expense, the total cost as it pertained to clip usage ($30.32 USD) was still lower than that using titanium clips ($139.17 USD). While these numbers were not statistically significant, three cases had bile leaks and required additional procedures, all of which were performed with metal clips. No postoperative bleeds were identified and there was no difference in hospital length of stay; most patients were discharged on the day of the procedure. CONCLUSION: These findings demonstrate comparable clinical outcomes between laparoscopic cholecystectomies performed with polymer and titanium clips, though polymer clip usage carries a lower cost.

Primary Uncomplicated Ventral Hernia Repair: Guidelines and Practice Patterns for Routine Hernia Repairs.

Surgical repair of primary umbilical and epigastric hernias are among the most common abdominal operations in the world. The hernia defects range from small (<1 cm) to large and complex even in the absence of prior incision or repair. Mesh has generally been shown to decrease recurrence rates, and its use and location of placement should be individualized for each patient. Open, laparoscopic, and robotic approaches provide unique considerations for the technical aspects of primary repair with or without mesh augmentation.

Pharmacodynamics of ATI-2307 in a rabbit model of cryptococcal meningoencephalitis.

Cryptococcal meningoencephalitis (CM) is a devastating fungal disease with high morbidity and mortality. The current regimen that is standard-of-care involves a combination of three different drugs administered for up to one year. There is a critical need for new therapies due to both toxicity and inadequate fungicidal activity of the currently available antifungal drugs. ATI-2307 is a novel aryl amidine that disrupts the mitochondrial membrane potential and inhibits the respiratory chain complexes of fungi-it thus represents a new mechanism for direct antifungal action. Furthermore, ATI-2307 selectively targets fungal mitochondria via a fungal-specific transporter that is not present in mammalian cells. It has very potent in vitro anticryptococcal activity. In this study, the efficacy of ATI-2307 was tested in a rabbit model of CM. ATI-2307 demonstrated significant fungicidal activity at dosages between 1 and 2 mg/kg/d, and these results were superior to fluconazole and similar to amphotericin B treatment. When ATI-2307 was combined with fluconazole, the antifungal effect was greater than either therapy alone. While ATI-2307 has potent anticryptococcal activity in the subarachnoid space, its ability to reduce yeasts in the brain parenchyma was relatively less over the same study period. This new drug, with its unique mechanism of fungicidal action and ability to positively interact with an azole, has demonstrated sufficient anticryptococcal potential in this experimental setting to be further evaluated in clinical studies.

The Role of Biologic Mesh and Fundoplication in the Surgical Management of Hiatal Hernias: A Multicenter Evaluation.

INTRODUCTION: Hiatal hernia repair is associated with substantial recurrence of both hiatal hernia and symptoms of gastroesophageal reflux (GER). While small randomized controlled trials demonstrate limited differences in outcomes with use of mesh or fundoplication type, uncertainty remains. METHODS: A multicenter, retrospective review of patients undergoing surgical treatment of hiatal hernias between 2015 and 2020 was performed. Patients with mesh and with suture-only repair were compared, and partial versus complete fundoplication was compared. Primary outcomes were hernia recurrence and occurrence of postoperative GER symptoms and dysphagia. Multivariable regression was performed to assess the effect of each intervention on clinical outcomes. RESULTS: A total of 453 patients from four sites were followed for a median (IQR) of 17 (13) months. On multivariate analysis, mesh had no impact on hernia recurrence (odds ratio 0.993, 95% CI: 0.53-1.87, p = 0.982), and fundoplication type did not impact recurrence of postoperative GER symptoms (complete: odds ratio 0.607, 95% CI: 0.33-1.12, p = 0.112) or dysphagia (complete: odds ratio 1.17, 95% CI: 0.56-2.43, p = 0.677). CONCLUSION: During hiatal hernia repair, mesh and fundoplication type do not appear to have substantial impact on GER symptoms, dysphagia, or hernia recurrence. This multicenter study provides real-world evidence to support the findings of small RCTs.

The Trauma Activation Review Committee: Response to Undertriage During a Period of Rapid Growth at a Level II Trauma Center.

Trauma triage criteria are constantly being refined for improved identification of severely injured patients. When errors occur, they should be tracked, and triage criteria adjusted to minimize these events. Two time periods of trauma registry data at a single rural level II trauma center were retrospectively compared to evaluate demographics, injuries, and outcomes to identify triage errors. In 300 activated trauma patients during 2011, overtriage was 23% and undertriage was 3.7%. In 1035 activated trauma patients during 2019, overtriage was 20.5% and undertriage was 2.2%. Mortality decreased over time overall. In 2019, Trauma I patients were older, spent more time on the ventilator, and in the ICU (all P < .001). Trauma II patients were also older, had lower ISS, hospital days, and ventilator days (all P < .001). During rapid growth, evaluation of overtriage and undertriage can provide useful feedback for hospital staff to refine triage choices and improve patient outcomes.

Inferior Epigastric Artery Pseudoaneurysm Following Laparoscopic Appendectomy.

An inferior epigastric artery pseudoaneurysm is an exceptionally rare occurrence. Formation of an inferior epigastric artery pseudoaneurysm can be seen following surgical intervention and is more common after laparoscopy. A sixty-eight-year-old male presented with a right upper quadrant bulge at his incision site two months following laparoscopic appendectomy. The patient reported sudden onset of a non-reducible bulge at a 5 mm trocar incision site with minimal pain and without obstructive symptoms. Computed tomography of his abdomen and pelvis with intravenous contrast revealed a 4.2 cm pseudoaneurysm with peripheral thrombosis within the right inferior epigastric artery. The patient subsequently underwent open exploration with the evacuation of pseudoaneurysm thrombus and ligation of arteriovenous fistula. The patient recovered well without complication from pseudoaneurysm. Inferior epigastric artery pseudoaneurysm following any laparoscopic procedure is rare. This case highlights the importance of understanding the abdominal wall anatomy and its vascular supply to avoid such injury. We present this case to bring light to this rare occurrence and to highlight the importance of proper trocar placement during any laparoscopic procedure.

Food and Drug Administration Public Workshop Summary-Development Considerations of Antifungal Drugs to Address Unmet Medical Need.

Pressing challenges in the treatment of invasive fungal infections (IFIs) include emerging and rare pathogens, resistant/refractory infections, and antifungal armamentarium limited by toxicity, drug-drug interactions, and lack of oral formulations. Development of new antifungal drugs is hampered by the limitations of the available diagnostics, clinical trial endpoints, prolonged trial duration, difficulties in patient recruitment, including subpopulations (eg, pediatrics), and heterogeneity of the IFIs. On 4 August 2020, the US Food and Drug Administration convened a workshop that included IFI experts from academia, industry, and other government agencies to discuss the IFI landscape, unmet need, and potential strategies to facilitate the development of antifungal drugs for treatment and prophylaxis. This article summarizes the key topics presented and discussed during the workshop, such as incentives and research support for drug developers, nonclinical development, clinical trial design challenges, lessons learned from industry, and potential collaborations to facilitate antifungal drug development.

Teaching Small Bite Fascial Closure Technique: Improved Accuracy and Consistency Through Simulation.

Despite evidence that small bite closure is beneficial, it is not well documented how accurately and consistently surgeons employ this technique. We created a felt model to simulate fascial closure and educate residents regarding small bites. This study aims to gauge accuracy and consistency of bite size in fascial closure and assess if utilizing a templated model could improve technique. Two 10 cm incisions were made in different pieces of felt. Residents were instructed to suture the incisions to simulate fascial closure by running the incisions closed with 1 cm and 5 mm bites respectively. The process was repeated with templated pieces of felt marking 1 and 0.5 cm to guide bite size. Residents were timed for each closure. The travel and distance from the midline for each bite was measured and analysis performed. 14 residents participated. Paired T-test compared means and standard deviations of bite size. Taking 5 mm bites took more time. Standard deviation of travel and right sided distance from midline were significantly smaller when a template was utilized. Standard deviation of travel as well as right sided distance was also improved when instructed to take 5 mm bites. This study demonstrates that a small bite technique results more closure and that when residents are instructed to take smaller bites. The adage, "aim small, miss small," holds true in fascial closure and may be one reason why small bites improve hernia rates. This study also suggests that the use of a template improves accuracy and consistency of closure regardless of bite size intention.

Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.

BACKGROUND: There are limited data describing clinical flucytosine pharmacokinetics (PK). The variability of flucytosine partitioning into the CNS is not known. We described the interindividual variability in flucytosine PK in patients with HIV-associated cryptococcal meningoencephalitis. In addition, we quantified the extent and variability of CSF partitioning of flucytosine. METHODS: A PK study was conducted in 64 patients with confirmed HIV-associated cryptococcal meningoencephalitis in Blantyre, Malawi. A four-compartment PK model was developed, and Monte Carlo simulations were performed with flucytosine administered at different doses and in different schedules. RESULTS: The estimated mean apparent volume of the central compartment was 17.50 (SD 9.99) L; mean apparent clearance was 5.88 (SD 3.35) L/h; mean apparent volume of the CNS compartment was 41.73 (SD 13.66) L. From the Bayesian posterior estimates, AUC24 values at steady state (144-168 h) with doses of 25 mg/kg q6h were median (IQR) 890.38 (603.81-1213.70) mg.h/L in plasma and 595.66 (425.69-776.64) mg.h/L in CSF. The ratio of CSF:plasma AUC24 was 0.69 (IQR 0.58-0.82). CONCLUSIONS: This study revealed significant interindividual variability in flucytosine PK in plasma and CSF in patients with HIV-associated cryptococcal meningoencephalitis. The population PK model is a first critical step for revised flucytosine regimens that maximize fungal killing and minimize toxicity and the emergence of resistance.

Assessment of Antifungal Pharmacodynamics.

Pharmacokinetic-pharmacodynamic (PK-PD) analysis is of central importance to the progress of an antifungal agent into clinical use. It is crucial to ensure that preclinical studies give the best possible prediction of the way drugs are likely to behave in a clinical setting. This review details the last 30 years of progress in terms of disease model design, efficacy outcome selection and translational modelling in antifungal PK-PD studies. The principles of how PK-PD parameters inform current clinical practice are also discussed, including a review of how these apply to existing and novel agents.