Enhanced Recovery after Surgery (ERAS) Protocols Expanded over Multiple Service Lines Improves Patient Care and Hospital Cost.

Enhanced recovery after surgery (ERAS) may improve patients' postoperative course. Our center implemented the ERAS protocol for the colorectal service in 2016, and then expanded to multiple service lines over the course of 1.5 years. Our aim was to determine whether broad implementation of ERAS protocols across different service lines could improve patient care. All ERAS patients from 2018 were captured prospectively. For each service line using ERAS, one full year of data preceding ERAS was compared. ERAS service lines included colorectal, gynecology laparoscopic, gynecology open, hepatopancreaticobiliary, urology - nephrectomy and cystectomy, spinal fusion, cardiac surgery-coronary artery bypass grafting. ERAS and pre-ERAS services were compared based on length of stay (LOS), complications, readmission, and mortality rates. In addition, hospital costs were collected during this time frame. ERAS protocols significantly decreased LOS for colorectal, gynecology, and spine. Complications were significantly decreased in colorectal, gynecology, urology, and spine. Readmissions did not significantly increase in any service line except spine. There was no significant change in mortality. ERAS proved to save the hospital 1847 days and cost saving of almost $5 million in 2018. Implementing ERAS broadly improved patient outcomes (LOS, complications, readmission, and mortality) while providing cost savings to the hospital.

A Preliminary Assessment of Abdominal Wall Tension in Patients Undergoing Retromuscular Hernia Repair.

A common technique for ventral and incisional hernia repair is the retrorectus repair (Rives-Stoppa). The posterior rectus sheath is incised bilaterally, and mesh is placed retromuscularly. There is little information on how this component separation technique affects abdominal wall tension. We evaluated abdominal wall tension in patients undergoing retrorectus repair of abdominal wall hernias. Patients undergoing retrorectus repair of their ventral hernias were enrolled in a prospective, Institutional Review Board-approved protocol to measure abdominal wall tension from 8/1/2013 to 8/2/2017. Demographic information and operative details were documented. Abdominal wall tensions were measured using scales attached to Kocher clamps that were clamped to the fascia and brought together in the midline. Measurements were made before and after incising the posterior rectus sheaths. Data were analyzed with a repeated measures analysis of variance (ANOVA), and differences between individual groups were analyzed by least square differences. Forty-five patients had tension measurements. Average age was 58 years (range 29-81)-78% Caucasian, 51% female, an average body mass index (BMI) of 35 kg/m2 (range 20-62), and 38% recurrent hernias. The average hernia defect was 121.9 cm2, and the average mesh size was 607.8 cm2. There was a significant reduction in tension after bilateral posterior rectus sheath incision (3.1 lbs vs. 5.6 lbs, p<0.0001). In this evaluation, abdominal wall tension measurements are shown to be a feasible adjunct during open hernia repair with retrorectus repair. Transection of the posterior rectus sheath decreases tension during hernia repair and may help guide surgeons regarding when to use this procedure.

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.

Incisional Hernia in the United States: Trends in Hospital Encounters and Corresponding Healthcare Charges.

Incisional hernia (IH) is a challenging, potentially morbid condition. This study evaluates recent trends in hospital encounters associated with IH care in the United States. Using Nationwide Inpatient Sample databases from 2007 to 2011, annual estimates of IH-related hospital discharges, charges, and serious adverse events were identified. Significance in observed trends was tested using regression modeling. From 2007 to 2011, there were 583,054 hospital discharges associated with a diagnosis of IH. 81.1 per cent had a concurrent procedure for IH repair. The average discharge included a female patient (63.2%), 59.8 years of age, with either Medicare (45.3%) or Private insurance (38.3%) as the anticipated primary payer. Comparing 2007 to 2011, significant increases in IH discharges (12%; 2007 = 109,702 vs 2011 = 123,034, P = 0.009) and IH repairs (10%; 2007 = 90,588 vs 2011 = 99,622, P < 0.001) were observed. This was accompanied by a 37 per cent increase in hospital charges (2007 = $44,587 vs 2011 = $60,968, P < 0.001), resulting in a total healthcare bill of $7.3 billion in 2011. Significant trends toward greater patient age (2007 = 59.7 years vs 2011 = 60.2 years, P < 0.001), higher comorbidity index (2007 = 3.0 vs 2011 = 3.5, P < 0.001), and increased frequency of serious adverse events (2007 = 13.5% vs 2011 = 17.7%, P < 0.001) were noted. Further work is needed to identify interventions to mitigate the risk of IH development.

Endpoint Assessment in Rabbit Models of Invasive Pulmonary Aspergillosis and Mucormycosis.

Multiple animal models have been developed to study the pathogenesis of invasive pulmonary aspergillosis, as well as to evaluate the efficacy, pharmacokinetics, and pharmacodynamics of various antifungal agents and vaccines. Each model is beneficial depending on the questions that are asked. In this chapter, we will discuss the endpoints assessment of the persistently neutropenic rabbit models of invasive pulmonary aspergillosis and invasive pulmonary mucormycosis.

Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints.

OBJECTIVES: Isavuconazole, a novel triazole antifungal agent, has broad-spectrum activity against Aspergillus spp. and other pathogenic fungi. The isavuconazole exposure-response relationship in experimental invasive pulmonary aspergillosis using galactomannan index (GMI) suppression as a marker of disease clearance was explored. METHODS: The impact of exposure on GMI suppression in persistently neutropenic rabbits treated with isavuconazonium sulphate (isavuconazole-equivalent dosages of 20, 40 or 60 mg/kg every 24 h, after a 90 mg/kg loading dose) for 12 days was linked using mathematical modelling. Bridging to humans using population pharmacokinetic (PK) data from a clinical trial in invasive aspergillosis was performed using Monte Carlo simulations. RESULTS: Mean plasma isavuconazole AUC/MIC (EC50) of 79.65 (95% CI 32.2, 127.1) produced a half-maximal effect in GMI suppression. The inhibitory sigmoid Emax curve dropped sharply after an AUC/MIC of ≥30 and was near maximum (EC80) at ∼130. Bridging the experimental PK/pharmacodynamic (PD) target to human population PK data was then used to return to the rabbit model to determine a clinically relevant PD endpoint. The clinical dosing regimen used in the trial would result in a mean GMI of 4.3 ±â€Š1.8, which is a 50% reduction from the starting GMI in the experiment. CONCLUSIONS: The clinical trial results showing the non-inferiority of isavuconazole to voriconazole for all-cause mortality further support the PK-PD endpoint, thereby demonstrating the usefulness of the rabbit model and endpoint for isavuconazole and implications on interpretive breakpoints. Importantly, the analysis supports this model as an important tool for development of antifungal agents.

Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B against Aspergillus fumigatus.

Amphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1 → 3)-ß-D-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the "average" patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1 → 3)-ß-D-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1 → 3)-ß-D-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1 → 3)-ß-D-glucan levels in the majority of patients.

Plasma and target-site subcutaneous tissue population pharmacokinetics and dosing simulations of cefazolin in post-trauma critically ill patients.

OBJECTIVES: The objective of this study was to describe the population pharmacokinetics of cefazolin in plasma and the interstitial fluid of subcutaneous tissue of post-trauma critically ill patients and provide clinically relevant dosing recommendations that result in optimal concentrations at the target site. PATIENTS AND METHODS: This was a pharmacokinetic study in a tertiary referral ICU. We recruited 30 post-trauma critically ill adult patients and collected serial total and unbound plasma cefazolin concentrations. Interstitial fluid concentrations were determined using in vivo microdialysis. Population pharmacokinetic analysis and Monte Carlo simulations were undertaken with Pmetrics(®). Fractional target attainment against an MIC distribution for Staphylococcus aureus isolates was calculated. RESULTS: The mean (SD) age, weight, APACHE II score and CLCR were 37.0 (14.1) years, 86.8 (22.7) kg, 16.9 (5.3) and 163 (44) mL/min, respectively. A three-compartment linear population pharmacokinetic model was most appropriate. Covariates included in the model were CLCR on drug clearance and serum albumin concentration and body weight on the volume of the central compartment. The fractional target attainment for a 1 g intravenous 8-hourly dose for a CLCR of 50 mL/min was 88%, whereas for a patient with a CLCR of 215 mL/min, a dose of 2 g 6-hourly achieved 84% fractional target attainment. CONCLUSIONS: Clinicians should be mindful of the effects of elevated CLCR and serum albumin concentrations on dosing requirements for post-trauma critically ill patients.

Anidulafungin for neonatal hematogenous Candida meningoencephalitis: identification of candidate regimens for humans using a translational pharmacological approach.

Hematogenous Candida meningoencephalitis (HCME) is a serious infection in premature neonates. Anidulafungin is an echinocandin antifungal agent with potent activity against Candida spp., but its efficacy and optimal regimens for human neonates with HCME are not known. A well-validated rabbit model of HCME was used to define pharmacokinetic-pharmacodynamic (PK-PD) relationships of anidulafungin. A mathematical model was fitted to the entire data set. The experimental data were bridged to humans. A population PK model was fitted to the data from human neonates receiving anidulafungin receiving a loading dose of 3 mg/kg, followed by 1.5 mg/kg/day. Monte Carlo simulations were performed to identify candidate anidulafungin regimens for humans. All untreated rabbits succumbed by ≤96 h postinoculation. The PK of anidulafungin was linear with dose-dependent penetration into the cerebrum. Anidulafungin exerted a rapid antifungal effect that was apparent in the first dosing interval. Near-maximal antifungal activity was observed with dosages of 10 to 20 mg/kg/day. The bridging studies suggested that the current regimen of first 3 mg/kg, followed by 1.5 mg/kg/day, is suboptimal. Higher dosages were associated with progressively greater antifungal effect. Anidulafungin is effective for the treatment of experimental HCME. Higher dosages than those currently used for clinical care are required for maximal antifungal effect.

Population pharmacokinetics of voriconazole in adults.

Voriconazole is a first-line agent for the treatment of invasive fungal infections. The pharmacology of voriconazole is characterized by extensive interindividual variability and nonlinear pharmacokinetics. The population pharmacokinetics of voriconazole in 64 adults is described. The patient population consisted of 21 healthy volunteers, who received a range of intravenous (i.v.) and oral voriconazole regimens, and 43 patients with proven or probable invasive aspergillosis, who received the currently licensed dosage. Voriconazole concentrations were measured using high-performance liquid chromatography (HPLC). The pharmacokinetic data were modeled using a nonparametric methodology and with a nonlinear pharmacokinetic structural model. The extent and consequences of pharmacokinetic variability were explored using Monte Carlo simulation. The relationship between drug exposure and clinical response was explored using logistic regression. Optimal sampling times were identified using D-optimal design. The fit of the nonlinear model was acceptable. Data from the healthy volunteers provided robust estimates for K(m) and the maximum rate of enzyme activity (V(max)). The Bayesian parameter estimates were more variable and statistically different in patients than in volunteers. There was a linear relationship between the trough concentration and area under the concentration-time curve (AUC(0-12)). There was no relationship between the AUC(0-12) and clinical response. The original parameter values were readily recapitulated using Monte Carlo simulation. Initial i.v. dosing resulted in higher AUC(0-12) and trough concentrations compared with oral dosing. Sample collection times of 1, 2, 3, 4, 8, and 12 h after an i.v. infusion are maximally informative times for future pharmacokinetic studies.

Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients.

Voriconazole is approved for treating invasive fungal infections. We examined voriconazole exposure-response relationships for patients from nine published clinical trials. The relationship between the mean voriconazole plasma concentration (C(avg)) and clinical response and between the free C(avg)/MIC ratio versus the clinical response were explored using logistic regression. The impact of covariates on response was also assessed. Monte Carlo simulation was used to estimate the relationship between the trough concentration/MIC ratio and the probability of response. The covariates individually related to response were as follows: study (P < 0.001), therapy (primary/salvage, P < 0.001), primary diagnosis (P < 0.001), race (P = 0.004), baseline bilirubin (P < 0.001), baseline alkaline phosphatase (P = 0.014), and pathogen (yeast/mold, P < 0.001). The C(avg) for 72% of the patients was 0.5 to 5.0 µg/ml, with the maximum response rate (74%) at 3.0 to 4.0 µg/ml. The C(avg) showed a nonlinear relationship to response (P < 0.003), with a lower probability at the extremes. For patients with C(avg) < 0.5 µg/ml, the response rate was 57%. The lowest response rate (56%) was seen with a C(avg) ≥ 5.0 µg/ml (18% of patients) and was associated with significantly lower mold infection responses compared to yeasts (P < 0.001) but not with voriconazole toxicity. Higher free C(avg)/MIC ratios were associated with a progressively higher probability of response. Monte Carlo simulation suggested that a trough/MIC ratio of 2 to 5 is associated with a near-maximal probability of response. The probability of response is lower at the extremes of C(avg). Patients with higher free C(avg)/MIC ratios have a higher probability of clinical response. A trough/MIC ratio of 2 to 5 can be used as a target for therapeutic drug monitoring.

Initial laparoscopic basic skills training shortens the learning curve of laparoscopic suturing and is cost-effective.

BACKGROUND: Laparoscopic suturing is an advanced skill that is difficult to acquire. Simulator-based skills curricula have been developed that have been shown to transfer to the operating room. Currently available skills curricula need to be optimized. We hypothesized that mastering basic laparoscopic skills first would shorten the learning curve of a more complex laparoscopic task and reduce resource requirements for the Fundamentals of Laparoscopic Surgery suturing curriculum. STUDY DESIGN: Medical students (n = 20) with no previous simulator experience were enrolled in an IRB-approved protocol, pretested on the Fundamentals of Laparoscopic Surgery suturing model, and randomized into 2 groups. Group I (n = 10) trained (unsupervised) until proficiency levels were achieved on 5 basic tasks; Group II (n = 10) received no basic training. Both groups then trained (supervised) on the Fundamentals of Laparoscopic Surgery suturing model until previously reported proficiency levels were achieved. Two weeks later, they were retested to evaluate their retention scores, training parameters, instruction requirements, and cost between groups using t-test. RESULTS: Baseline characteristics and performance were similar for both groups, and 9 of 10 subjects in each group achieved the proficiency levels. The initial performance on the simulator was better for Group I after basic skills training, and their suturing learning curve was shorter compared with Group II. In addition, Group I required less active instruction. Overall time required to finish the curriculum was similar for both groups; but the Group I training strategy cost less, with a savings of $148 per trainee. CONCLUSIONS: Teaching novices basic laparoscopic skills before a more complex laparoscopic task produces substantial cost savings. Additional studies are needed to assess the impact of such integrated curricula on ultimate educational benefit.

Population pharmacokinetics of micafungin in neonates and young infants.

Micafungin is an echinocandin with potent activity against Candida spp. Hematogenous Candida meningoencephalitis (HCME) is a frequent complication of disseminated Candida infection in premature infants. A preclinical model of HCME suggests that micafungin may be an effective agent for this syndrome, but relatively high weight-based dosages are required. This prompted the further study of the safety and pharmacokinetics (PK) of micafungin in infants. Here, we describe the population pharmacokinetics of micafungin in 47 infants with a proven or presumptive diagnosis of disseminated candidiasis, who received 0.75, 1.5, 3, 7, 10, and 15 mg/kg of micafungin. The drug was infused daily, and samples were taken in the first dosing interval and at steady state. Serum concentrations were measured using high-performance liquid chromatography (HPLC). Data were modeled using an allometric pharmacokinetic model using a three-fourths scaling exponent for clearance and parameters normalized to a 70-kg adult. Drug exposures were estimated using Monte Carlo simulation. Optimal sampling times were determined using D-optimal design theory. The fit of the allometric model to the data was highly acceptable. The pharmacokinetics of micafungin were linear. The weight-normalized estimates of clearance and volume of distribution approximated those previously described for adults. The original population parameter values could be recapitulated in the Monte Carlo simulations. A dosage of 10 mg/kg/day resulted in 82.6% of patients with areas under the concentration-time curve (AUCs) that are associated with near-maximal decline in fungal burden within the central nervous system (CNS).

Comparison of generic versus specific quality-of-life scales for mesh hernia repairs.

BACKGROUND: With the use of mesh shown to considerably reduce recurrence rates for hernia repair and the subsequent improvement in clinical outcomes, focus has now been placed on quality-of-life outcomes in patients undergoing these repairs, specifically, as they relate to the mesh prosthesis. Traditionally, quality of life after hernia surgery, like many other medical conditions, has been tested using the generic SF-36 survey. The SF-36 quality-of-life survey, although well studied and validated, may not be ideal for patients undergoing hernia repairs. We propose a new quality-of-life survey, the Carolinas Comfort Scale (CCS), pertaining specifically to patients undergoing hernia repair with mesh; our goal was to test the validity and reliability of this survey. STUDY DESIGN: The CCS questionnaire was mailed to 1,048 patients to assess its acceptability, responsiveness, and psychometric properties. The survey sample included patients who were at least 6 months out after hernia repair with mesh. Patients were asked to fill out the CCS and the generic SF-36 questionnaires, four questions comparing the two surveys, and their overall satisfaction relating to their hernia repair and mesh. RESULTS: The reliability of the CCS was confirmed by Cronbach's alpha coefficient (0.97). Test-retest validity was supported by the correlation found between two different administrations of the CCS; both Spearman's correlation coefficient and the kappa coefficient were important for each question of the CCS. Assessment of its discriminant validity showed that both the mean and median scores for satisfied patients were considerably lower than those for dissatisfied patients. Concurrent validity was demonstrated by the marked correlations found between the CCS and SF-36 questionnaire scales. When comparing the two surveys, 72% of patients preferred the CCS questionnaire, 80% believed it was easier to understand, 66% thought it was more reflective of their condition, and 69% said they would rather fill it out over the SF-36. CONCLUSIONS: The CCS better assesses quality of life and satisfaction of patients who have undergone surgical hernia repair than the generic SF-36.

The pharmacokinetics and pharmacodynamics of micafungin in experimental hematogenous Candida meningoencephalitis: implications for echinocandin therapy in neonates.

BACKGROUND: Hematogenous Candida meningoencephalitis (HCME) is a relatively frequent manifestation of disseminated candidiasis in neonates and is associated with significant mortality and neurodevelopmental abnormalities. The outcome after antifungal therapy is often suboptimal, with few therapeutic options. Limited clinical data suggest that echinocandins may have role to play in the treatment of HCME. METHODS: We studied the pharmacokinetics and pharmacodynamics of micafungin in a rabbit model of neonatal HCME and bridged the results to neonates by use of population pharmacokinetics and Monte Carlo simulation. RESULTS: Micafungin exhibited linear plasma pharmacokinetics in the range of 0.25-16 mg/kg. Micafungin penetrated most compartments of the central nervous system (CNS), but only with doses >2 mg/kg. Micafungin was not reliably found in cerebrospinal fluid. With few exceptions, drug penetration into the various CNS subcompartments was not statistically different between infected and noninfected rabbits. A dose-microbiological response relationship was apparent in the brain, and near-maximal effect was apparent with doses of 8 mg/kg. Monte Carlo simulations revealed that near-maximal antifungal effect was attained at human neonatal doses of 12-15 mg/kg. CONCLUSIONS: These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.

Optimization of the dosage of flucytosine in combination with amphotericin B for disseminated candidiasis: a pharmacodynamic rationale for reduced dosing.

Amphotericin B and flucytosine (5FC) have an additive effect when used for disseminated candidiasis. Here, we bridge the results of an experimental pharmacodynamic study to humans and demonstrate that a 5FC dosage of 25 mg/kg of body weight/day in four divided doses in combination with amphotericin B produces near-maximal effect.

Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing.

The echinocandins potentially have an important role in treatment of infections caused by Candida spp. and Aspergillus spp. in immunocompromised children. However, there are no population pharmacokinetic models of the echinocandins for pediatric patients. The safety and descriptive pharmacokinetics of micafungin in children were recently reported. However, a population pharmacokinetic model in children is needed in order to accurately determine the dosage of micafungin that produces an equivalent magnitude of drug exposure to that observed in adults. In order to explore the effect of weight on micafungin pharmacokinetics, a standard two-compartment pharmacokinetic model, a linear model, and an allometric power model were developed. For all three models, the fit to the data was excellent, with comparable measures of precision and bias. However, the superior log-likelihood value of the allometric power model suggested that it best reflected the data and was therefore chosen for a more detailed analysis of the magnitude and pattern of drug exposure which develop following the administration of micafungin. The allometric power model suggested that clearance in smaller children is higher than that predicted on the basis of weight alone. Consequently, a degree of dosage increase is required in smaller children to ensure comparable levels of drug exposure to those observed in larger children and adults. The allometric power model developed in this study enables identification of pediatric dosage regimens of micafungin which, based upon Monte Carlo simulations, result in equivalent drug exposures to those observed in adults, for which antifungal efficacy has been established.

Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: implications for antifungal therapy.

BACKGROUND: Little is known about the pathogenesis of invasive pulmonary aspergillosis and the relationship between the kinetics of diagnostic markers and the outcome of antifungal therapy. METHODS: An in vitro model of the human alveolus, consisting of a bilayer of human alveolar epithelial and endothelial cells, was developed. An Aspergillus fumigatus strain expressing green fluorescent protein was used. Invasion of the cell bilayer was studied using confocal and electron microscopy. The kinetics of culture, polymerase chain reaction, and galactomannan were determined. Galactomannan was used to measure the antifungal effect of macrophages and amphotericin B. A mathematical model was developed, and results were bridged to humans. RESULTS: A. fumigatus penetrated the cellular bilayer 14-16 h after inoculation. Galactomannan levels were inextricably tied to fungal invasion and were a robust measure of the antifungal effect of macrophages and amphotericin B. Neither amphotericin nor macrophages alone was able to suppress the growth of A. fumigatus; rather, the combination was required. Monte Carlo simulations showed that human dosages of amphotericin B of at least 0.6 mg/kg were required to achieve adequate drug exposure. CONCLUSIONS: This model provides a strategy by which relationships among pathogenesis, immunological effectors, and antifungal drug therapy for invasive pulmonary aspergillosis may be further understood.