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.

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.

The Hernia Coding Conundrum: A Potential Benefit of the International Hernia Collaboration Online Social Media Platform.

BACKGROUND: Despite various resources on the subject, there remain questions regarding billing and coding hernia surgery. Recently, social media has been used to disseminate information in about surgery. The purpose of this project is to evaluate posts relating to coding through one online social media platform. MATERIALS AND METHODS: The International Hernia Collaboration Facebook site was queried with terms relating to coding. Inclusion criteria were post discussing coding on the site. Posts relating to coding were reviewed by at least 2 reviewers. Number of comments, main topic of question, and additional information about codes were recorded and descriptive statistics generated. RESULTS: There were 100 posts found using the search term coding of which 85 met inclusion criteria. Post ranged from 5/2014 to 6/2021. Posts were from 72 surgeons with an average of 12 responses per post. Posts most commonly related to ventral and incisional hernia (53) followed by inguinal (18), other (19), diaphragm (4), and inguinal/ventral (1). For the ventral/incisional hernia, the most common posts were related to myofascial release techniques (29) followed by mesh (6), botox (5), hernia prevention (3), other (3), robotic surgery (2), open surgery (2), rectus diastasis (2), and laparoscopy (2). DISCUSSION: There remains controversies over coding for hernia repair particularly myofascial releases in ventral and incisional and new techniques using the robot. An online social media platform appears to be a viable way to disseminate coding information and generate discussion. Further study is needed to evaluate the role of social media for coding.

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.

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.

Potential Antibiotics for the Treatment of Neonatal Sepsis Caused by Multidrug-Resistant Bacteria.

Neonatal sepsis causes up to an estimated 680,000 deaths annually worldwide, predominantly in low- and middle-income countries (LMICs). A significant and growing proportion of bacteria causing neonatal sepsis are resistant to multiple antibiotics, including the World Health Organization-recommended empiric neonatal sepsis regimen of ampicillin/gentamicin. The Global Antibiotic Research and Development Partnership is aiming to develop alternative empiric antibiotic regimens that fulfil several criteria: (1) affordable in LMIC settings; (2) activity against neonatal bacterial pathogens, including extended-spectrum ß-lactamase producers, gentamicin-resistant Gram-negative bacteria, and methicillin-resistant Staphylococcus aureus (MRSA); (3) a licence for neonatal use or extensive experience of use in neonates; and (4) minimal toxicities. In this review, we identify five antibiotics that fulfil these criteria: amikacin, tobramycin, fosfomycin, flomoxef, and cefepime. We describe the available characteristics of each in terms of mechanism of action, resistance mechanisms, clinical pharmacokinetics, pharmacodynamics, and toxicity profile. We also identify some knowledge gaps: (1) the neonatal pharmacokinetics of cefepime is reliant on relatively small and limited datasets, and the pharmacokinetics of flomoxef are also reliant on data from a limited demographic range and (2) for all reviewed agents, the pharmacodynamic index and target has not been definitively established for both bactericidal effect and emergence of resistance, with many assumed to have an identical index/target to similar class molecules. These five agents have the potential to be used in novel combination empiric regimens for neonatal sepsis. However, the data gaps need addressing by pharmacokinetic trials and pharmacodynamic characterisation.

Amikacin Combined with Fosfomycin for Treatment of Neonatal Sepsis in the Setting of Highly Prevalent Antimicrobial Resistance.

Antimicrobial resistance (particularly through extended-spectrum ß-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16-arm dose-ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MICF × MICA < 256 (where MICF and MICA are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve >99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.

Cryptococcal meningoencephalitis: time for action.

Cryptococcal meningoencephalitis was first described over a century ago. This fungal infection is preventable and treatable yet continues to be associated with excessive morbidity and mortality. The largest burden of disease resides in people living with HIV in low-income and middle-income countries. In this group, mortality with the best antifungal induction regimen (7 days of amphotericin B deoxycholate [1·0 mg/kg per day] and flucytosine [100·0 mg/kg per day]) in a clinical trial setting was 24% at 10 weeks. The world is now at an inflection point in terms of recognition, research, and action to address the burden of morbidity and mortality from cryptococcal meningoencephalitis. However, the scope of interventional programmes needs to increase, with particular attention to implementation science that is specific to individual countries. This Review summarises causes of excessive mortality, interventions with proven survival benefit, and gaps in knowledge and practice that contribute to the ongoing high death toll from cryptococcal meningoencephalitis. TRANSLATIONS: For the Vietnamese and Chichewa translations of the abstract see Supplementary Materials section.

Prospective, multicenter study of P4HB (Phasix™) mesh for hernia repair in cohort at risk for complications: 3-Year follow-up.

BACKGROUND: This study represents a prospective, multicenter, open-label study to assess the safety, performance, and outcomes of poly-4-hydroxybutyrate (P4HB, Phasix™) mesh for primary ventral, primary incisional, or multiply-recurrent hernia in subjects at risk for complications. This study reports 3-year clinical outcomes. MATERIALS AND METHODS: P4HB mesh was implanted in 121 patients via retrorectus or onlay technique. Physical exam and/or quality of life surveys were completed at 1, 3, 6,12, 18, 24, and 36 months, with 5-year (60-month) follow-up ongoing. RESULTS: A total of n = 121 patients were implanted with P4HB mesh (n = 75 (62%) female) with a mean age of 54.7 ± 12.0 years and mean BMI of 32.2 ± 4.5 kg/m2 (±standard deviation). Comorbidities included: obesity (78.5%), active smokers (23.1%), COPD (28.1%), diabetes mellitus (33.1%), immunosuppression (8.3%), coronary artery disease (21.5%), chronic corticosteroid use (5.0%), hypo-albuminemia (2.5%), advanced age (5.0%), and renal insufficiency (0.8%). Hernias were repaired via retrorectus (n = 45, 37.2% with myofascial release (MR) or n = 43, 35.5% without MR), onlay (n = 8, 6.6% with MR or n = 24, 19.8% without MR), or not reported (n = 1, 0.8%). 82 patients (67.8%) completed 36-month follow-up. 17 patients (17.9% ± 0.4%) experienced hernia recurrence at 3 years, with n = 9 in the retrorectus group and n = 8 in the onlay group. SSI (n = 11) occurred in 9.3% ± 0.03% of patients. CONCLUSIONS: Long-term outcomes following ventral hernia repair with P4HB mesh demonstrate low recurrence rates at 3-year (36-month) postoperative time frame with no patients developing late mesh complications or requiring mesh removal. 5-year (60-month) follow-up is ongoing.

An Evaluation of Tension Measurements During Myofascial Release for Hernia Repair.

Tension-free repairs have revolutionized the way we repair hernias. To help reduce undue tension when performing ventral hernia repair, multiple different techniques of myofascial releases have been described. The purpose of this project is to evaluate tension measurements for commonly performed myofascial releases in abdominal wall hernia repair. Patients undergoing myofascial release techniques for their ventral hernias were enrolled in a prospective Institutional Review Board-approved protocol to measure abdominal wall tension from June 1, 2011 to August 1, 2019. Abdominal wall tensions were measured using tensiometers before and after myofascial release techniques. Descriptive statistics were performed and data were analyzed. Thirty patients had tension measurements (5 anterior myofascial separation, 25 posterior myofascial separation with transversus abdominis release [TAR]). Average age was 60.1 years (range 29-81), 83% Caucasian, 53% female, and 42% recurrent hernias. The average hernia defect in patients undergoing anterior myofascial release was 117.3 cm2, and the average mesh size was 650 cm2. The reduction in tension after anterior release was 4.7 lbs (2.7 lbs vs 7.4 lbs). The average hernia defect in patients undergoing posterior myofascial release (TAR) was 183 cm2, and the average mesh size was 761.36 cm2. The reduction in tension after bilateral posterior rectus sheath incision was 2.55 lbs (5.01 lbs vs 7.56 lbs) with 0.66 lbs further reduction in tension after TAR (4.35 lbs vs 5.01). In this evaluation, abdominal wall tension measurements are shown to be a feasible adjunct during open hernia repair. Preliminary data show tension reductions associated with the different myofascial release techniques and, with further study, may be a useful intraoperative adjunct for decision making in hernia repair.

Pharmacodynamics of the Novel Metallo-ß-Lactamase Inhibitor ANT2681 in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae.

Enterobacteriaceae that produce metallo-ß-lactamases (MBLs) are an emerging threat to public health. The metallo-ß-lactamase inhibitor (MBLi) ANT2681 inhibits the enzymatic activity of MBLs through interaction with the dinuclear zinc ion cluster present in the active site that is common to these enzymes. ANT2681 is being codeveloped, with meropenem as the partner ß-lactam, as a novel combination therapy for infections caused by MBL-producing bacteria. The pharmacokinetics/pharmacodynamics of meropenem-ANT2681 were studied in a murine neutropenic thigh model of NDM-producing Enterobacteriaceae Dose-ranging studies were performed with both meropenem and ANT2681. Dose fractionation experiments were performed to identify the relevant pharmacodynamic index of ANT2681 when coadministered with meropenem. A background of meropenem at 50 mg/kg of body weight every 4 h (q4h) subcutaneously (s.c.) had minimal antibacterial effect. On this background, half-maximal effect was observed with an ANT2681 dose of 89 mg/kg q4h intravenously (i.v.). The dose fractionation study showed that area under the concentration-time curve (AUC) was the relevant pharmacodynamic index for the inhibitor. The magnitude of the meropenem-ANT2681 exposure required to achieve stasis was explored using 5 NDM-producing strains. A 3-dimensional surface fitted to the pharmacodynamic data from the 5 strains suggested that stasis was achieved with an fT > potentiated meropenem MIC of 40% and ANT2681 AUC of 700 mg · h/liter. These data and analyses provide the underpinning evidence for the combined use of meropenem and ANT2681 for clinical infections.

Setting Our Sights on Infectious Diseases.

In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings.

Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance.

Cryptococcal meningitis is a lethal disease with few therapeutic options. Induction therapy with fluconazole has been consistently demonstrated to be associated with suboptimal microbiological and clinical outcomes. Exposure to fluconazole causes dynamic changes in antifungal susceptibility, which are associated with the development of aneuploidy. The implications of this phenomenon for pharmacodynamics of fluconazole for cryptococcal meningitis are poorly understood. The pharmacodynamics of fluconazole were studied using a hollow-fiber infection model (HFIM) and a well-characterized murine model of cryptococcal meningoencephalitis. The relationship between drug exposure and both antifungal killing and the emergence of resistance was quantified. The same relationships were further evaluated in a recently described group of patients with cryptococcal meningitis undergoing induction therapy with fluconazole at 800 to 1,200 mg/day. The pattern of emergence of fluconazole resistance followed an "inverted U." Resistance amplification was maximal and suppressed at ratios of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC:MIC) of 34.5 to 138 and 305.6, respectively. Emergence of resistance was observed in vivo with an fAUC:MIC of 231.4. Aneuploidy with duplication of chromosome 1 was demonstrated to be the underlying mechanism in both experimental models. The pharmacokinetic (PK)-pharmacodynamic model accurately described the PK, antifungal killing, and emergence of resistance. Monte Carlo simulations from the clinical pharmacokinetic-pharmacodynamic model showed that only 12.8% of simulated patients receiving fluconazole at 1,200 mg/day achieved sterilization of the cerebrospinal fluid (CSF) after 2 weeks and that 83.4% had a persistent subpopulation that was resistant to fluconazole. Fluconazole is primarily ineffective due to the emergence of resistance. Treatment with 1,200 mg/day leads to the killing of a susceptible subpopulation but is compromised by the emergence of resistance.IMPORTANCE Cryptococcal meningitis is a lethal disease with few treatment options. The incidence remains high and intricately linked with the HIV/AIDS epidemic. In many parts of the world, fluconazole is the only agent that is available for the initial treatment of cryptococcal meningitis despite considerable evidence that it is associated with suboptimal microbiological and clinical outcomes. Fluconazole has a fungistatic mode of action: it predominantly inhibits growth rather than causing fungal killing. Our work shows that the pattern of fluconazole activity is caused by the emergence of resistance in Cryptococcus not detected by standard susceptibility tests, with chromosomal duplication/aneuploidy as the main mechanism. Resistance emergence is related to drug exposure and occurs with the use of clinically relevant regimens. Hence, fluconazole (and potentially other agents that target 14-alpha-demethylase) is compromised by an intrinsic property that limits its effectiveness. However, this resistance may be potentially overcome by dosage escalation or the use of combination therapy.

Clinical Application of the Measurement of Abdominal Wall Tension in Hernia Repair.

Abdominal wall tension is an integral concept in hernia repair. Most of the described techniques attempt to reduce abdominal wall tension by using mesh prosthetics or myofascial release. Although the concept of a "tension-free" hernia repair is well-understood and appreciated by surgeons, quantitative information about abdominal wall tension is limited. This review evaluates the published literature related to abdominal wall tension and summarizes how the measurement of intraoperative tension can guide clinical decision-making. Most of the methods and techniques for measuring abdominal wall tension are similar and involve the use of tensiometers. However, there is no accepted standardized technique. Baseline tension measurements confirm the concept of a baseline physiological tension, and it has been observed that tension does not correlate with hernia width. When the tension is considered to be too great during hernia repair, intraoperative techniques such as myofascial release can be used to reduce tension to physiological values. Emerging data from clinical studies on tension have added to our understanding of the mechanics and physiology of the abdominal wall. Standardized devices and measurement techniques need to be developed and validated to foster the utility of tension measurements in hernia repair.

Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections.

Tebipenem pivoxil HBr (TBPM-PI-HBr) is a novel orally bioavailable carbapenem. The active moiety is tebipenem. Tebipenem pivoxil is licensed for use in Japan in children with ear, nose, and throat infections and respiratory infections. The HBr salt was designed to improve drug substance and drug product properties, including stability. TBPM-PI-HBr is now being developed as an agent for the treatment of complicated urinary tract infections (cUTI) in adults. The pharmacokinetics-pharmacodynamics of tebipenem were studied in a well-characterized neutropenic murine thigh infection model. Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry. Dose fractionation experiments were performed after establishing dose-response relationships. The magnitude of drug exposure required for stasis was established using 11 strains of Enterobacteriaceae (Escherichia coli, n = 6; Klebsiella pneumoniae, n = 5) with a variety of resistance mechanisms. The relationship between drug exposure and the emergence of resistance was established in a hollow-fiber infection model (HFIM). Tebipenem exhibited time-dependent pharmacodynamics that were best described by the free drug area under the concentration-time curve (fAUC0-24)/MIC corrected for the length of the dosing interval (fAUC0-24/MIC · 1/tau). The pharmacodynamics of tebipenem versus E. coli and K. pneumoniae were comparable, as was the response of strains possessing extended-spectrum ß-lactamases versus the wild type. The median fAUC0-24/MIC · 1/tau value for the achievement of stasis in the 11 strains was 23. Progressively more fractionated regimens in the HFIM resulted in the suppression of resistance. An fAUC0-24/MIC · 1/tau value of 34.58 to 51.87 resulted in logarithmic killing and the suppression of resistance. These data and analyses will be used to define the regimen for a phase III study of adult patients with cUTI.

Population pharmacokinetics of continuous-infusion ceftazidime in febrile neutropenic children undergoing HSCT: implications for target attainment for empirical treatment against Pseudomonas aeruginosa.

OBJECTIVES: To conduct a population pharmacokinetic analysis of continuous-infusion ceftazidime in a retrospective cohort of paediatric HSCT patients who were empirically treated for febrile neutropenia (FN) and who underwent therapeutic drug monitoring of ceftazidime steady-state plasma concentrations (Css) for optimization of drug exposure. METHODS: A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed to calculate the PTA of the pharmacodynamic determinant of efficacy (Css/MIC ≥4) against Pseudomonas aeruginosa with continuous-infusion ceftazidime dosages of 1-6 g daily. The Css safety threshold was arbitrarily placed at 100 mg/L and advisable dosages were used. RESULTS: A total of 46 patients with 70 ceftazidime Css values were included. Estimated glomerular filtration rate (eGFR) and body surface area were the covariates associated with drug clearance. At the EUCAST clinical breakpoint of 8 mg/L, simulations showed that continuous-infusion ceftazidime dosages of 4-6 g daily attained optimal PTAs (>90%) across most of 16 different clinical scenarios based on four classes of eGFR (50-145, 145.1-200, 200.1-286 and 286.1-422 mL/min/1.73 m2) and body surface area (0.30-0.64, 0.65-0.88, 0.89-1.34 and 1.35-1.84 m2). In patients with body surface area 0.30-0.64 m2 and eGFR ≤200 mL/min/1.73 m2 the advisable dose of 3 g daily allowed only suboptimal PTAs (<75%). The cumulative fraction of response against MIC distribution of P. aeruginosa was >87%. CONCLUSIONS: Continuous-infusion ceftazidime dosages ranging from 3 to 6 g daily according to different classes of eGFR and body surface area may allow optimized empirical treatment of P. aeruginosa infections in paediatric HSCT patients with FN.

Outcomes by MIC Values for Patients Treated with Isavuconazole or Voriconazole for Invasive Aspergillosis in the Phase 3 SECURE and VITAL Trials.

This pooled analysis evaluated the relationship of isavuconazole and voriconazole MICs of Aspergillus pathogens at baseline with all-cause mortality and clinical outcomes following treatment with either drug in the SECURE and VITAL trials. Isavuconazole and voriconazole may have had reduced efficacy against pathogens with drug MICs of ≥16 µg/ml, but there was no relationship with clinical outcomes in cases where the MIC was <16 µg/ml for either drug.

Population Pharmacodynamics of Amphotericin B Deoxycholate for Disseminated Infection Caused by Talaromyces marneffei.

Amphotericin B deoxycholate (DAmB) is a first-line agent for the initial treatment of talaromycosis. However, little is known about the population pharmacokinetics and pharmacodynamics of DAmB for talaromycosis. Pharmacokinetic data were obtained from 78 patients; among them, 55 patients had serial fungal CFU counts in blood also available for analysis. A population pharmacokinetic-pharmacodynamic model was fitted to the data. The relationships between the area under the concentration-time curve (AUC)/MIC and the time to blood culture sterilization and the time to death were investigated. There was only modest pharmacokinetic variability in the average AUC, with a mean ± standard deviation of 11.51 ± 3.39 mg·h/liter. The maximal rate of drug-induced kill was 0.133 log10 CFU/ml/h, and the plasma concentration of the DAmB that induced the half-maximal rate of kill was 0.02 mg/liter. Fifty percent of patients sterilized their bloodstreams by 83.16 h (range, 13 to 264 h). A higher initial fungal burden was associated with a longer time to sterilization (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.36 to 0.70; P < 0.001). There was a weak relationship between AUC/MIC and the time to sterilization, although this did not reach statistical significance (HR, 1.03; 95% CI, 1.00 to 1.06, P = 0.091). Furthermore, there was no relationship between the AUC/MIC and time to death (HR, 0.97; 95% CI, 0.88 to 1.08; P = 0.607) or early fungicidal activity {slope = log[(0.500 - 0.003·(AUC/MIC)]; P = 0.319} adjusted for the initial fungal burden. The population pharmacokinetics of DAmB are surprisingly consistent. The time to sterilization of the bloodstream may be a useful pharmacodynamic endpoint for future studies. (This study has been registered at the ISRCTN registry under no. ISRCTN59144167.).

Exposure-Response Analysis of Micafungin in Neonatal Candidiasis: Pooled Analysis of Two Clinical Trials.

BACKGROUND: Neonatal candidiasis causes significant morbidity and mortality in high risk infants. The micafungin dosage regimen of 10 mg/kg established for the treatment of neonatal candidiasis is based on a laboratory animal model of neonatal hematogenous Candida meningoencephalitis and pharmacokinetic (PK)-pharmacodynamic (PD) bridging studies. However, little is known about the how these PK-PD data translate clinically. METHODS: Micafungin plasma concentrations from infants were used to construct a population PK model using Pmetrics software. Bayesian posterior estimates for infants with invasive candidiasis were used to evaluate the relationship between drug exposure and mycologic response using logistic regression. RESULTS: Sixty-four infants 3-119 days of age were included, of which 29 (45%) infants had invasive candidiasis. A 2-compartment PK model fits the data well. Allometric scaling was applied to clearance and volume normalized to the mean population weight (kg). The mean (standard deviation) estimates for clearance and volume in the central compartment were 0.07 (0.05) L/h/1.8 kg and 0.61 (0.53) L/1.8 kg, respectively. No relationship between average daily area under concentration-time curve or average daily area under concentration-time curve:minimum inhibitory concentration ratio and mycologic response was demonstrated (P > 0.05). Although not statistically significant, mycologic response was numerically higher when area under concentration-time curves were at or above the PD target. CONCLUSIONS: While a significant exposure-response relationship was not found, PK-PD experiments support higher exposures of micafungin in infants with invasive candidiasis. More patients would clarify this relationship; however, low incidence deters the feasibility of these studies.

Pharmacodynamics of Voriconazole for Invasive Pulmonary Scedosporiosis.

Scedosporium apiospermum is a medically important fungal pathogen that causes a wide range of infections in humans. There are relatively few antifungal agents that are active against Scedosporium spp. Little is known about the pharmacodynamics of voriconazole against Scedosporium Both static and dynamic in vitro models of invasive scedosporiosis were developed. Monoclonal antibodies that target a soluble cell wall antigen secreted by Scedosporium apiospermum were used to describe the pharmacodynamics of voriconazole. Mathematical pharmacokinetic-pharmacodynamic models were fitted to the data to estimate the drug exposure required to suppress the release of fungal antigen. The experimental results were bridged to humans using Monte Carlo simulation. All 3 strains of S. apiospermum tested invaded through the cellular bilayer of the in vitro models and liberated antigen. There was a concentration-dependent decline in the amount of antigen, with near maximal antifungal activity against all 3 strains being achieved with voriconazole at 10 mg/liter. Similarly, there was a drug exposure-dependent decline in the amount of circulating antigen in the dynamic model and complete suppression of antigen, with an area under the concentration-time curve (AUC) of approximately 80 mg · h/liter. A regression of the AUC/MIC versus the area under the antigen-time curve showed that a near maximal effect was obtained with an AUC/MIC of approximately 100. Monte Carlo simulation suggested that only isolates with an MIC of 0.5 mg/liter enabled pharmacodynamic targets to be achieved with a standard regimen of voriconazole. Isolates with higher MICs may need drug exposure targets higher than those currently recommended for other fungi.