Research prioritization in hernia surgery: a modified Delphi ACHQC and VHOC expert consensus.

PURPOSE: Numerous clinical practice guidelines and consensus statements have been published in hernia surgery, however, there is still a need for high-quality evidence to address remaining unanswered questions. The aim of this study was to conduct research priority setting through a modified Delphi process to identify a list of top research priorities in hernia surgery. METHODS: A structured literature review of clinical practice guidelines was performed by the steering committee. Topics considered clinically significant, practical to study and lacking strong evidence were extracted and refined into a comprehensive list, then entered into a two-round Delphi survey for prioritization at the Abdominal Core Health Quality Collaborative (ACHQC) Quality Improvement Summit. In round 1, participants were instructed to select any topic that should be prioritized for future research. Topics were ranked according to the proportion of votes and the 25 highest-ranking topics were included in the second round. In round 2, participants were instructed to select only the top 10 topics for research prioritization. RESULTS: Eleven clinical practice guidelines were reviewed. Eighty-seven topics were extracted by the steering committee and submitted for prioritization. After the first round, 25 of the highest-ranking topics were determined and included in the second round. A final list of 11 research questions was identified. The hernia types with the most research interest were inguinal and epigastric/umbilical hernias. Other topics of high interest were the management of diastasis recti, primary versus mesh repairs and expectant management versus surgical repair. CONCLUSION: Our study provides a research agenda generated through expert consensus that may be used in the prioritization of the design and funding of clinical trials in hernia surgery.

Retrorectus Ventral Hernia Repair Utilizing T-line Hernia Mesh: Technical Descriptions.

The T-line hernia mesh is a synthetic, polypropylene mesh with mesh suture extensions designed to prevent anchor point failure by evenly distributing tension across the soft tissue. Previous studies have demonstrated the success of onlay ventral hernia repair with T-line hernia mesh, but retrorectus applications of the mesh have not yet been characterized. This technique article illustrates technical descriptions and clinical applications of the T-line hernia mesh in the retrorectus plane.

Biomarker Driven Antifungal Stewardship (BioDriveAFS) in acute leukaemia-a multi-centre randomised controlled trial to assess clinical and cost effectiveness: a study protocol for a randomised controlled trial.

BACKGROUND: Acute leukaemias (AL) are life-threatening blood cancers that can be potentially cured with treatment involving myelosuppressive, multiagent, intensive chemotherapy (IC). However, such treatment is associated with a risk of serious infection, in particular invasive fungal infection (IFI) associated with prolonged neutropenia. Current practice guidelines recommend primary antifungal (AF) prophylaxis to be administered to high-risk patients to reduce IFI incidence. AFs are also used empirically to manage prolonged neutropenic fever. Current strategies lead to substantial overuse of AFs. Galactomannan (GM) and ß-D-glucan (BG) biomarkers are also used to diagnose IFI. Combining both biomarkers may enhance the predictability of IFI compared to administering each test alone. Currently, no large-scale randomised controlled trial (RCT) has directly compared a biomarker-based diagnostic screening strategy without AF prophylaxis to AF prophylaxis (without systematic biomarker testing). METHODS: BioDriveAFS is a multicentre, parallel, two-arm RCT of 404 participants from UK NHS Haematology departments. Participants will be allocated on a 1:1 basis to receive either a biomarker-based antifungal stewardship (AFS) strategy, or a prophylactic AF strategy, which includes existing standard of care (SoC). The co-primary outcomes will be AF exposure in the 12-month post randomisation and the patient-reported EQ-5D-5L measured at 12-month post randomisation. Secondary outcomes will include total AF exposure, probable/proven IFI, survival (all-cause mortality and IFI mortality), IFI treatment outcome, AF-associated adverse effects/events/complications, resource use, episodes of neutropenic fever requiring hospital admission or outpatient management, AF resistance in fungi (non-invasive and invasive) and a Desirability of Outcome Ranking. The trial will have an internal pilot phase during the first 9 months. A mixed methods process evaluation will be integrated in parallel to the internal pilot phase and full trial, aiming to robustly assess how the intervention is delivered. Cost-effectiveness analysis will also be performed. DISCUSSION: The BioDriveAFS trial aims to further the knowledge of strategies that will safely optimise AF use through comparison of the clinical and cost-effectiveness of a biomarker-led diagnostic strategy versus prophylactic AF to prevent and manage IFI within acute leukaemia. The evidence generated from the study will help inform global clinical practice and approaches within antifungal stewardship. TRIAL REGISTRATION: ISRCTN11633399. Registered 24/06/2022.

Ventral Hernia Reconstruction with GORE ENFORM Biomaterial.

Introduction: Ventral hernia repair (VHR) is one of the most common surgeries performed in the United States. Degradable mesh is the recommended choice for patients presenting with high-risk co-morbidities or increased risk for infection. GORE® ENFORM BiomaterialTM is a biosynthetic degradable mesh that has recently been approved for use in ventral hernia reconstruction with no reports of its clinical outcomes. Methods: This study was a single surgeon case series. Patients were included in the study if they underwent VHR with GORE® ENFORM BiomaterialTM. The decision to use GORE® ENFORM BiomaterialTM was the senior surgeon's decision based on the patient's center for disease control classification. Patient comorbidities, hernia characteristics, postoperative hernia recurrence, and surgical site occurrences (SSOs) were collected at in-patient follow-up appointments and chart review. Patients were asked to complete preoperative and postoperative patient-reported outcomes (PROs) using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Intensity short form 3a and the hernia-specific quality of life (HerQLes) survey. Results: A total of 15 patients were included in this study. The average length of follow-up was 315 days. Postoperatively, 26.7% of patients had an SSO with 4 surgical site infections. Two patients required an operative washout with mesh removal. One patient experienced hernia recurrence. Eight of the 15 patients completed preoperative and postoperative PROs. Conclusion: This is the first clinical study to report the outcomes of ventral hernia repair using ENFORM mesh. These results show that Enform mesh is an option to consider in complex ventral hernia reconstruction.

Introduction: La réparation d'une hernie ventrale (RHV) est l'une des opérations les plus fréquentes aux États-Unis. Le treillis dégradable est le choix recommandé pour les patients ayant des affections connexes à haut risque ou qui sont vulnérables aux infections. Le biomatériau GORE® ENFORM est un treillis biosynthétique dégradable qui a récemment été approuvé pour la reconstruction des hernies ventrales et dont les résultats cliniques n'ont fait l'objet d'aucun rapport. Méthodologie : La présente étude était constituée d'une série de cas réalisée par un seul chirurgien. Les patients étaient inclus dans l'étude s'ils avaient subi une RHV à l'aide de biomatériau GORE® ENFORM. Le chirurgien en chef prenait la décision d'utiliser ce biomatériau d'après la classification du contrôle des maladies au centre du patient. Les chercheurs ont colligé les affections connexes du patient, les caractéristiques de la hernie, les récurrences de hernie postopératoire et les occurrences au foyer de l'opération (OFO) lors des rendez-vous de suivi et de l'examen des dossiers. Les patients ont été invités à préciser leurs résultats préopératoires et postopératoires (RPP) au moyen du formulaire court 3a sur l'intensité de la douleur tiré du système d'information des mesures de résultats déclarés par le patient (PROMIS) et du sondage sur la qualité de vie propre à la hernie (HerQLes). Résultats : Au total, 15 patients ont participé à l'étude et ont été suivis pendant une durée moyenne de 315 jours. Après l'opération, 26,7% des patients ont présenté une OFO ainsi que quatre infections au foyer de l'opération. Deux patients ont eu besoin d'un lessivage opératoire et du retrait du treillis. Un patient a subi une récurrence de la hernie. Huit des 15 patients ont rempli les RDP avant et après l'opération. Conclusion : Il s'agit de la première étude clinique à déclarer les résultats cliniques de la réparation d'une hernie ventrale à l'aide du treillis ENFORM. Ces résultats démontrent que le treillis Enform peut être envisagé pour la reconstruction d'une hernie ventrale complexe.

State of the Art: Advances in Hernia Care.

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.

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.

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.

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.

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.

Evaluation of ICARUS Guidelines and Recommendations Not Supported by Randomized Controlled Trials.

BACKGROUND: The ICARUS guidelines are a systematic review and Delphi process that provide recommendations in the treatment and management of patients with gastroesophageal reflux disease (GERD). Many of the recommendations were supported by randomized trials; some were not. This study assesses guidelines with limited evidence and weak endorsement. METHODS: Four ICARUS guidelines were chosen: the role of fundoplication for patients with BMI > 35, regurgitation, chest pain, and extra-esophageal symptoms. A multicenter database of patients undergoing fundoplication surgery for GERD between 2015 and 2020 was used. Outcomes assessed were anatomic failure and symptom recurrence. Multivariable regression was performed. RESULTS: Five institutions performed a fundoplication on 461 patients for GERD with a median of follow-up of 14.7 months (IQR 14.2). On multivariate analysis, patients with the chosen pre-operative comorbidities achieved comparable post-operative benefits. Patients with a BMI > 35 were not more likely to experience anatomic failure. Patients with pre-operative regurgitation had similar symptom recurrence rates to those without. Patients with non-cardiac chest pain had comparable rates of symptom recurrence to those without. Reporting a pre-operative chronic cough attributable to reflux was not associated with higher rates of post-operative symptom recurrence. DISCUSSION: Among the ICARUS guidelines and recommendations, a small proportion was lacking evidence at low risk for bias and endorsement. The results of this multicenter study evaluated outcomes of patients with various pre-operative conditions: BMI > 35, chest pain attributable to reflux, extra-esophageal symptoms attributable to reflux, and regurgitation. Our findings endorse patients with these characteristics as candidates for anti-reflux surgery.

Laparoscopic versus robotic inguinal hernia repair: 1- and 2-year outcomes from the RIVAL trial.

INTRODUCTION: Robotic inguinal hernia repair is growing in popularity among general surgeons despite little high-quality evidence supporting short- or long-term advantages over traditional laparoscopic inguinal hernia repair. The original RIVAL trial showed increased operative time, cost, and surgeon frustration for the robotic approach without advantages over laparoscopy. Here we report the 1- and 2-year outcomes of the trial. METHODS: This is a multi-center, patient-blinded, randomized clinical study conducted at six sites from 2016 to 2019, comparing laparoscopic versus robotic transabdominal preperitoneal (TAPP) inguinal hernia repair with follow-up at 1 and 2 years. Outcomes include pain (visual analog scale), neuropathic pain (Leeds assessment of neuropathic symptoms and signs pain scale), wound morbidity, composite hernia recurrence (patient-reported and clinical exam), health-related quality of life (36-item short-form health survey), and physical activity (physical activity assessment tool). RESULTS: Early trial participation included 102 patients; 83 (81%) completed 1-year follow-up (45 laparoscopic vs. 38 robotic) and 77 (75%) completed 2-year follow-up (43 laparoscopic vs. 34 robotic). At 1 and 2 years, pain was similar for both groups. No patients in either treatment arm experienced neuropathic pain. Health-related quality of life and physical activity were similar for both groups at 1 and 2 years. No long-term wound morbidity was seen for either repair type. At 2 years, there was no difference in hernia recurrence (1 laparoscopic vs. 1 robotic; P = 1.0). CONCLUSIONS: Laparoscopic and robotic inguinal hernia repairs have similar long-term outcomes when performed by surgeons with experience in minimally invasive inguinal hernia repairs.

Expert Consensus for Key Features of Operative Reports of Ventral Hernia.

BACKGROUND: Operative reports are important documents; however, standards for critical elements of operative reports are general and often vague. Hernia surgery is one of the most common procedures performed by general surgeons, so the aim of this project was to develop a Delphi consensus on critical elements of a ventral hernia repair operative report. STUDY DESIGN: The Delphi method was used to establish consensus on key features of operative reports for ventral hernia repair. An expert panel was selected and questionnaires were distributed. The first round of voting was open-ended to allow participants to recommend what details should be included. For the second round the questionnaire was distributed with the items that did not have unanimous responses along with free text comments from the first round. RESULTS: Eighteen surgeons were approached, of which 11 completed both rounds. Twenty items were on the initial questionnaire, of which 11 had 100% agreement. Of the remaining 9 items, after the second questionnaire an additional 7 reached consensus. CONCLUSION: Ventral hernia repairs are a common and challenging problem and often require reoperations. Surgeons frequently refer to previous operative notes to guide future procedures, which requires detailed and comprehensive operative reports. This Delphi consensus was able to identify key components needed for an operative report describing ventral hernia repair.

Educating Residents in Abdominal Wall Closure: An Overview.

Background and Aims: Incisional hernia prevention has become an important concept for surgeons operating on the abdominal wall. Several techniques have been proposed to help decrease incisional hernia formation with suture closure of the abdominal wall being one of the cornerstones. Technical details that have been reported to decrease incisional hernia rates include achieving a 4:1 Suture to Wound length ratio and the use of a small bites technique. Despite evidence to support many of these techniques there appears to be a gap in practice patterns amongst practicing surgeons. Introducing and promoting these principles in surgical residency may help to close this gap. This paper reviews our experience with surgical training for abdominal wall closures at our institution. Materials and Methods: Programs and projects related to abdominal wall closure were reviewed from our institution from 2010-Present. Type of project, intervention, and impact on education was evaluated and summarized. Results: Seven projects were identified relating to surgical training and abdominal wall closure. Three projects dealt with skills training using an abdominal wall simulation model and related to suturing techniques. Two projects were clinical studies focused on suture to wound length ratios and improving outcomes with this variable in a residency training program. Two projects dealt with models relating to abdominal wall closure and education. Conclusion: Implementation of educational programs in surgical residency programs can lead to improvements in technique and knowledge around abdominal wall closure and help in research endeavors.

Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis.

BACKGROUND: Single, high-dose liposomal amphotericin B (LAmB; AmBisome, Gilead Sciences) has demonstrated non-inferiority to amphotericin B deoxycholate in combination with other antifungals for averting all-cause mortality from HIV-associated cryptococcal meningitis. There are limited data on the pharmacokinetics (PK) of AmBisome. The aim of this study was to describe population PK of AmBisome and conduct a meta-analysis of the available studies to suggest the optimal dosing for cryptococcal meningoencephalitis. METHODS: Data from a Phase II and Phase III trial of high-dose, short-course AmBisome for cryptococcal meningoencephalitis were combined to develop a population PK model. A search was conducted for trials of AmBisome monotherapy and meta-analysis of clinical outcome data was performed. RESULTS: A two-compartment model with first-order clearance of drug from the central compartment fitted the data best and enabled the extent of inter-individual variability in PK to be quantified. Mean (SD) population PK parameter estimates were: clearance 0.416 (0.363)  L/h; volume of distribution 4.566 (4.518) L; first-order transfer of drug from central to peripheral compartments 2.222 (3.351)  h-1, and from peripheral to central compartment 2.951 (4.070)  h-1. Data for the meta-analysis were insufficient to suggest optimal dosing of AmBisome for cryptococcal meningoencephalitis. CONCLUSIONS: This study provides novel insight into the PK of AmBisome at the population level and the variability therein. Our analysis also serves to highlight the paucity of data available on the pharmacodynamics (PD) of AmBisome and underscores the importance of thorough and detailed PK/PD analysis in the development of novel antifungals, by demonstrating the challenges associated with post hoc PK/PD analysis.

Efficacy of APX2039 in a Rabbit Model of Cryptococcal Meningitis.

Cryptococcal Meningitis (CM) is uniformly fatal if not treated, and treatment options are limited. We previously reported on the activity of APX2096, the prodrug of the novel Gwt1 inhibitor APX2039, in a mouse model of CM. Here, we investigated the efficacy of APX2039 in mouse and rabbit models of CM. In the mouse model, the controls had a mean lung fungal burden of 5.95 log10 CFU/g, whereas those in the fluconazole-, amphotericin B-, and APX2039-treated mice were 3.56, 4.59, and 1.50 log10 CFU/g, respectively. In the brain, the control mean fungal burden was 7.97 log10 CFU/g, while the burdens were 4.64, 7.16, and 1.44 log10 CFU/g for treatment with fluconazole, amphotericin B, and APX2039, respectively. In the rabbit model of CM, the oral administration of APX2039 at 50 mg/kg of body weight twice a day (BID) resulted in a rapid decrease in the cerebrospinal fluid (CSF) fungal burden, and the burden was below the limit of detection by day 10 postinfection. The effective fungicidal activity (EFA) was -0.66 log10 CFU/mL/day, decreasing from an average of 4.75 log10 CFU/mL to 0 CFU/mL, over 8 days of therapy, comparing favorably with good clinical outcomes in humans associated with reductions of the CSF fungal burden of -0.4 log10 CFU/mL/day, and, remarkably, 2-fold the EFA of amphotericin B deoxycholate in this model (-0.33 log10 CFU/mL/day). A total drug exposure of the area under the concentration-time curve from 0 to 24 h (AUC0-24) of 25 to 50 mg · h/L of APX2039 resulted in near-maximal antifungal activity. These data support the further preclinical and clinical evaluation of APX2039 as a new oral fungicidal monotherapy for the treatment of CM. IMPORTANCE Cryptococcal meningitis (CM) is a fungal disease with significant global morbidity and mortality. The gepix Gwt1 inhibitors are a new class of antifungal drugs. Here, we demonstrated the efficacy of APX2039, the second member of the gepix class, in rabbit and mouse models of cryptococcal meningitis. We also analyzed the drug levels in the blood and cerebrospinal fluid in the highly predictive rabbit model and built a mathematical model to describe the behavior of the drug with respect to the elimination of the fungal pathogen. We demonstrated that the oral administration of APX2039 resulted in a rapid decrease in the CSF fungal burden, with an effective fungicidal activity of -0.66 log10 CFU/mL/day, comparing favorably with good clinical outcomes in humans associated with reductions of -0.4 log10 CFU/mL/day. The drug APX2039 had good penetration of the central nervous system and is an excellent candidate for future clinical testing in humans for the treatment of CM.