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.

Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

BACKGROUND: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known. METHODS: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin. RESULTS: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%). CONCLUSIONS: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).

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.

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.

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.

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.

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.

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.

OXA-48-Like ß-Lactamases: Global Epidemiology, Treatment Options, and Development Pipeline.

Modern medicine is threatened by the rising tide of antimicrobial resistance, especially among Gram-negative bacteria, where resistance to ß-lactams is most often mediated by ß-lactamases. The penicillin and cephalosporin ascendancies were, in their turn, ended by the proliferation of TEM penicillinases and CTX-M extended-spectrum ß-lactamases. These class A ß-lactamases have long been considered the most important. For carbapenems, however, the threat is increasingly from the insidious rise of a class D carbapenemase, OXA-48, and its close relatives. Over the past 20 years, OXA-48 and "OXA-48-like" enzymes have proliferated to become the most prevalent enterobacterial carbapenemases across much of Europe, Northern Africa, and the Middle East. OXA-48-like enzymes are notoriously difficult to detect because they often cause only low-level in vitro resistance to carbapenems, meaning that the true burden is likely underestimated. Despite this, they are associated with carbapenem treatment failures. A highly conserved incompatibility complex IncL plasmid scaffold often carries blaOXA-48 and may carry other antimicrobial resistance genes, leaving limited treatment options. High conjugation efficiency means that this plasmid is sometimes carried by multiple Enterobacterales in a single patient. Producers evade most ß-lactam-ß-lactamase inhibitor combinations, though promising agents have recently been licensed, notably ceftazidime-avibactam and cefiderocol. The molecular machinery enabling global spread, current treatment options, and the development pipeline of potential new therapies for Enterobacterales that produce OXA-48-like ß-lactamases form the focus of this review.

Pharmacodynamics of Meropenem and Tobramycin for Neonatal Meningoencephalitis: Novel Approaches to Facilitate the Development of New Agents to Address the Challenge of Antimicrobial Resistance.

Neonatal sepsis is an underrecognized burden on health care systems throughout the world. Antimicrobial drug resistance (AMR) is increasingly prevalent and compromises the use of currently recommended first-line agents. The development of new antimicrobial agents for neonates and children is mandated by regulatory agencies. However, there remains uncertainty about suitable development pathways, especially because of the propensity of premature babies to develop meningoencephalitis as a complication of neonatal sepsis and difficulties studying this disease in clinical settings. We developed a new platform and approach to accelerate the development of antimicrobial agents for neonatal bacterial meningoencephalitis using Pseudomonas aeruginosa as the challenge organism. We defined the pharmacodynamics of meropenem and tobramycin in these models. The percentage of partitioning of meropenem and tobramycin into the cerebrospinal fluid was comparable at 14.3 and 13.7%, respectively. Despite this similarity, there were striking differences in their pharmacodynamics. Meropenem resulted in bactericidal activity in both the cerebrospinal fluid and cerebrum, whereas tobramycin had minimal antibacterial activity. A hollow fiber infection model (HFIM) using neonatal CSF concentration time profiles yielded pharmacodynamics comparable to those observed in the rabbit model. These new experimental models can be used to estimate the pharmacodynamics of currently licensed agents and those in development and their potential efficacy for neonatal bacterial meningoencephalitis.

Flomoxef for neonates: extending options for treatment of neonatal sepsis caused by ESBL-producing Enterobacterales.

BACKGROUND: Neonatal sepsis is a serious and frequently lethal infection, often complicated by antimicrobial resistance (including ESBLs) in low- and middle-income countries (LMICs). Flomoxef is an off-patent oxacephem ß-lactam with stability against non-AmpC ESBLs, with potential for utility in these settings. To date, there has been no published flomoxef neonatal population pharmacokinetic (PopPK) model. OBJECTIVES: To summarize the clinical data available for flomoxef, build a neonatal PopPK model and assess the adequacy of different neonatal flomoxef regimens. METHODS: A systematic literature search returned all available clinical or pharmacokinetic data of flomoxef use in neonates. Pharmacokinetic data were used to construct a PopPK model, with progressive incorporation of covariates into the final model. Monte Carlo simulations were performed using this final model to simulate drug exposures of different flomoxef regimens to calculate PTAs. RESULTS: Individual-level clinical and pharmacokinetic data were extracted for 313 and 146 neonates, respectively, with population clinical data extracted for a further 199 neonates. Clinical and microbiological success rates were 89.71% and 82.8%, respectively, with minimal side effects. The final PopPK model incorporated body weight and postnatal age as covariates. PTA analyses predicted that IV regimens of 20 mg/kg q12h, 20 mg/kg q6-8h and 40 mg/kg q6-8h are adequate for neonates aged 0-7, 7-14 and 14-28 days, respectively. CONCLUSIONS: To the best of our knowledge, this is the first published neonatal PopPK model for flomoxef. Given the high treatment success rates, low toxicity rates and off-patent status, this drug has potential for use in the treatment of neonatal sepsis in ESBL-prevalent LMIC settings.

Addition of probenecid to oral ß-lactam antibiotics: a systematic review and meta-analysis.

OBJECTIVES: To explore the literature comparing the pharmacokinetic and clinical outcomes from adding probenecid to oral ß-lactams. METHODS: Medline and EMBASE were searched from inception to December 2021 for all English language studies comparing the addition of probenecid (intervention) with an oral ß-lactam [flucloxacillin, penicillin V, amoxicillin (±â€Šclavulanate), cefalexin, cefuroxime axetil] alone (comparator). ROBINS-I and ROB-2 tools were used. Data on antibiotic therapy, infection diagnosis, primary and secondary outcomes relating to pharmacokinetics and clinical outcomes, plus adverse events were extracted and reported descriptively. For a subset of studies comparing treatment failure between probenecid and control groups, meta-analysis was performed. RESULTS: Overall, 18/295 (6%) screened abstracts were included. Populations, methodology and outcome data were heterogeneous. Common populations included healthy volunteers (9/18; 50%) and those with gonococcal infection (6/18; 33%). Most studies were crossover trials (11/18; 61%) or parallel-arm randomized trials (4/18; 22%). Where pharmacokinetic analyses were performed, addition of probenecid to oral ß-lactams increased total AUC (7/7; 100%), Cmax (5/8; 63%) and serum t½ (6/8; 75%). Probenecid improved PTA (2/2; 100%). Meta-analysis of 3105 (2258 intervention, 847 control) patients treated for gonococcal disease demonstrated a relative risk of treatment failure in the random-effects model of 0.33 (95% CI 0.20-0.55; I2 = 7%), favouring probenecid. CONCLUSIONS: Probenecid-boosted ß-lactam therapy is associated with improved outcomes in gonococcal disease. Pharmacokinetic data suggest that probenecid-boosted oral ß-lactam therapy may have a broader application, but appropriately powered mechanistic and efficacy studies are required.

Standard ganciclovir dosing results in slow decline of cytomegalovirus viral loads.

BACKGROUND: Cytomegalovirus (CMV) can cause severe disease, including rejection in transplant recipients. Ganciclovir and its oral prodrug valganciclovir have been used as first-line therapy for CMV disease in transplant recipients. The exposure targets of ganciclovir are not exactly known, and toxicity and resistance have interfered with ganciclovir therapy. OBJECTIVES: To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ganciclovir in transplant recipients. METHODS: We used patient data from a previous observational study on ganciclovir therapeutic drug monitoring (TDM) in prophylaxis and therapy. The ganciclovir concentrations and CMV viral loads were determined during routine clinical care. The PK/PD population modelling and simulations were done with non-parametric methodology using the Pmetrics program. RESULTS: Eighty-five patients were included in the PK modelling. The final PK model was a two-compartment model with first-order absorption and elimination. A subset of 17 patients on CMV therapy were included in the PD modelling. A median of 4 (range 2-8) viral loads were obtained per patient. A simulation of 10 000 patients showed that an approximately 1 log10 reduction of CMV viral load will be observed after 12.5 days at the current recommended dose. CONCLUSIONS: The developed linked PK/PD population model and subsequent PD simulations showed slow decline of CMV viral load and it appears that dosing of (val)ganciclovir in this study might have been inadequate to achieve fast reduction of viral load. It is clear that further studies are needed to specify the PD effects of ganciclovir by performing systematic measurements of both ganciclovir concentrations and CMV viral loads.

Flomoxef and fosfomycin in combination for the treatment of neonatal sepsis in the setting of highly prevalent antimicrobial resistance.

BACKGROUND: Neonatal sepsis is a serious bacterial infection of neonates, globally killing up to 680 000 babies annually. It is frequently complicated by antimicrobial resistance, particularly in low- and middle-income country (LMIC) settings with widespread resistance to the WHO's recommended empirical regimen of ampicillin and gentamicin. OBJECTIVES: We assessed the utility of flomoxef and fosfomycin as a potential alternative empirical regimen for neonatal sepsis in these settings. METHODS: We studied the combination in a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment and chequerboard assays. We further assessed the combination using clinically relevant regimens in the HFIM with six Enterobacterales strains with a range of flomoxef/fosfomycin MICs. RESULTS: Pharmacokinetic/pharmacodynamic modelling of the HFIM experimental output, along with data from chequerboard assays, indicated synergy of this regimen in terms of bacterial killing and prevention of emergence of fosfomycin resistance. Flomoxef monotherapy was sufficient to kill 3/3 strains with flomoxef MICs ≤0.5 mg/L to sterility. Three of three strains with flomoxef MICs ≥8 mg/L were not killed by fosfomycin or flomoxef monotherapy; 2/3 of these were killed with the combination of the two agents. CONCLUSIONS: These data suggest that flomoxef/fosfomycin could be an efficacious and synergistic regimen for the empirical treatment of neonatal sepsis in LMIC settings with prevalent antimicrobial resistance. Our HFIM results warrant further assessment of the flomoxef/fosfomycin combination in clinical trials.

Assessment of flomoxef combined with amikacin in a hollow-fibre infection model for the treatment of neonatal sepsis in low- and middle-income healthcare settings.

BACKGROUND: Annual mortality from neonatal sepsis is an estimated 430 000-680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO currently recommends a narrow-spectrum ß-lactam (e.g. ampicillin) and gentamicin as first-line empirical therapy. However, available epidemiological data demonstrate high rates of resistance to both agents. Alternative empirical regimens are needed. Flomoxef and amikacin are two off-patent antibiotics with potential for use in this setting. OBJECTIVES: To assess the pharmacodynamics of flomoxef and amikacin in combination. METHODS: The pharmacodynamic interaction of flomoxef and amikacin was assessed in chequerboard assays and a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment. The combination was further assessed in HFIM experiments mimicking neonatal plasma exposures of clinically relevant doses of both drugs against five Enterobacterales isolates with a range of flomoxef/amikacin MICs. RESULTS: Flomoxef and amikacin in combination were synergistic in bacterial killing in both assays and prevention of emergence of amikacin resistance in the HFIM. In the HFIM assessing neonatal-like drug exposures, the combination killed 3/5 strains to sterility, (including 2/5 that monotherapy with either drug failed to kill) and failed to kill the 2/5 strains with flomoxef MICs of 32 mg/L. CONCLUSIONS: We conclude that the combination of flomoxef and amikacin is synergistic and is a potentially clinically effective regimen for the empirical treatment of neonatal sepsis in LMIC settings and is therefore suitable for further assessment in a clinical trial.

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.

Updated guideline for closure of abdominal wall incisions from the European and American Hernia Societies.

BACKGROUND: Incisional hernia is a frequent complication of abdominal wall incision. Surgical technique is an important risk factor for the development of incisional hernia. The aim of these updated guidelines was to provide recommendations to decrease the incidence of incisional hernia. METHODS: A systematic literature search of MEDLINE, Embase, and Cochrane CENTRAL was performed on 22 January 2022. The Scottish Intercollegiate Guidelines Network instrument was used to evaluate systematic reviews and meta-analyses, RCTs, and cohort studies. The GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation) was used to appraise the certainty of the evidence. The guidelines group consisted of surgical specialists, a biomedical information specialist, certified guideline methodologist, and patient representative. RESULTS: Thirty-nine papers were included covering seven key questions, and weak recommendations were made for all of these. Laparoscopic surgery and non-midline incisions are suggested to be preferred when safe and feasible. In laparoscopic surgery, suturing the fascial defect of trocar sites of 10 mm and larger is advised, especially after single-incision laparoscopic surgery and at the umbilicus. For closure of an elective midline laparotomy, a continuous small-bites suturing technique with a slowly absorbable suture is suggested. Prophylactic mesh augmentation after elective midline laparotomy can be considered to reduce the risk of incisional hernia; a permanent synthetic mesh in either the onlay or retromuscular position is advised. CONCLUSION: These updated guidelines may help surgeons in selecting the optimal approach and location of abdominal wall incisions.

An incisional hernia results from a weakness of the abdominal wall muscles that allows fat from the inside or organs to bulge out. These hernias are quite common after abdominal surgery at the site of a previous incision. There is research that discusses different ways to close an incision and this may relate to the chance of hernia formation. The aim of this study was to review the latest research and to provide a guide for surgeons on how best to close incisions to decrease hernia rates. When possible, surgery through small incisions may decrease the risk of hernia formation. If small incisions are used, it may be better if they are placed away from areas that are already weak (such as the belly button). If the incision is larger than 1 cm, it should be closed with a deep muscle-fascia suture in addition to skin sutures. If there is a large incision in the middle of the abdomen, the muscle should be sutured using small stitches that are close together and a slowly absorbable suture should be used. For patients who are at higher risk of developing hernias, when closing the incision, the muscle layer can be strengthened by using a piece of (synthetic) mesh. There is no good research available on recovery after surgery and no clear guides on activity level or whether a binder will help prevent hernia formation.

A Multicenter Analysis of the Early Impact of COVID-19 on Junior Resident Operative Case Volume.

INTRODUCTION: Institutions have reported decreases in operative volume due to COVID-19. Junior residents have fewer opportunities for operative experience and COVID-19 further jeopardizes their operative exposure. This study quantifies the impact of the COVID-19 pandemic on resident operative exposure using resident case logs focusing on junior residents and categorizes the response of surgical residency programs to the COVID-19 pandemic. MATERIALS AND METHODS: A retrospective multicenter cohort study was conducted; 276,481 case logs were collected from 407 general surgery residents of 18 participating institutions, spanning 2016-2020. Characteristics of each institution and program changes in response to COVID-19 were collected via surveys. RESULTS: Senior residents performed 117 more cases than junior residents each year (P < 0.001). Prior to the pandemic, senior resident case volume increased each year (38 per year, 95% confidence interval 2.9-74.9) while junior resident case volume remained stagnant (95% confidence interval 13.7-22.0). Early in the COVID-19 pandemic, junior residents reported on average 11% fewer cases when compared to the three prior academic years (P = 0.001). The largest decreases in cases were those with higher resident autonomy (Surgeon Jr, P = 0.03). The greatest impact of COVID-19 on junior resident case volume was in community-based medical centers (246 prepandemic versus 216 during pandemic, P = 0.009) and institutions which reached Stage 3 Program Pandemic Status (P = 0.01). CONCLUSIONS: Residents reported a significant decrease in operative volume during the 2019 academic year, disproportionately impacting junior residents. The long-term consequences of COVID-19 on junior surgical trainee competence and ability to reach cases requirements are yet unknown but are unlikely to be negligible.

Review of SAGES GERD guidelines and recommendations.

BACKGROUND: The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) developed evidence-based guidelines for the management of patients with gastroesophageal reflux disease (GERD). The aim of this study is to evaluate guidelines lacking agreement among experts (grades B-D) or lacking support from randomized controlled trials (levels II-III). METHODS: Six guidelines were chosen for evaluation. A retrospective review of a multicenter database of patients undergoing fundoplication surgery for treatment of GERD between 2015 and 2020 was performed. Patients that underwent a concurrent gastrectomy or were diagnosed with pre-operative achalasia were excluded. Demographics, pre-operative, intra-operative, and post-operative variables were collected. Post-operative outcomes were evaluated based on selected SAGES guidelines. Outcomes were assessed using multivariable regression or stratified analysis for each guideline. RESULTS: A total of 444 patients from four institutions underwent surgery for the management of GERD with a median (interquartile range) follow-up of 16 (13) months. Guidelines supported by our data were (1) robotic repair has similar short-term outcomes to laparoscopic repair, (2) outcomes in older patients are similar to outcomes of younger patients undergoing antireflux surgery, and (3) following laparoscopic antireflux surgery, dysphagia has been reported to significantly improve from pre-operative values. Guidelines that were not supported were (1) mesh reinforcement may be beneficial in decreasing the incidence of wrap herniation, (2) a bougie has been found to be effective, and (3) the long-term effectiveness of fundoplication in obese individuals (BMI > 30) has been questioned due to higher failure rates. CONCLUSION: Many SAGES GERD guidelines not receiving Grade A or Level I recommendation are supported by large, multicenter database findings. However, further studies at low risk for bias are needed to further refine these guidelines.

The T-Line® Hernia Mesh, A Novel Mesh Uniquely Designed to Prevent Hernia Recurrence and Occurrence.

Ventral hernia repair (VHR) fixation techniques with current meshes on the market are prone to failure from intra-abdominal pressure spikes due to coughing or lifting, for example. The T-Line® Hernia Mesh (Deep Blue Medical Advances, Durham, North Carolina) is a new mesh with a novel fixation mechanism to enhance anchoring strength addressing hernia occurrence and recurrence. Used similarly to traditional mesh, the new mesh uses incorporated mesh sutures that are 15 times the surface area of sutures for fixation rather than monofilament sutures, providing ~275% stronger anchoring strength. The increased surface area of the mesh extensions decreases tension on the mesh and tissue and increases the strength of the repair overall. There is also the likelihood that anchoring gains strength over time as the extensions undergo bioincorporation. This novel mesh specifically addresses the most common complication of VHR and has the potential to significantly improve outcomes.