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Despite implementing hundreds of strategies, cancer drug development suffers from a 95% failure rate over 30 years, with only 30% of approved cancer drugs extending patient survival beyond 2.5 months. Adding more criteria without eliminating nonessential ones is impractical and may fall into the “survivorship bias” trap. Machine learning (ML) models may enhance efficiency by saving time and cost. Yet, they may not improve success rate without identifying the root causes of failure. We propose a “STAR-guided ML system” (structure–tissue/cell selectivity–activity relationship) to enhance success rate and efficiency by addressing three overlooked interdependent factors: potency/specificity to the on/off-targets determining efficacy in tumors at clinical doses, on/off-target-driven tissue/cell selectivity influencing adverse effects in the normal organs at clinical doses, and optimal clinical doses balancing efficacy/safety as determined by potency/specificity and tissue/cell selectivity. STAR-guided ML models can directly predict clinical dose/efficacy/safety from five features to design/select the best drugs, enhancing success and efficiency of cancer drug development.

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Persistent atrial fibrillation (AF) is a complex arrhythmia, and attaining freedom from AF with ablation has been challenging.

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nab-Paclitaxel (nab-P), an albumin-bound formulation of paclitaxel, was developed to improve the tolerability and antitumor activity of taxanes. The neonatal Fc receptor (FcRn) is a transport protein that can bind to albumin and regulate the homeostasis of circulating albumin. Therefore, the pharmacokinetics and pharmacodynamics of nab-P may be impacted by FcRn expression. This study aimed to investigate the effects of FcRn on nab-P elimination and distribution to targeted tissues. Wild-type and FcRn-knockout (FcRn-KO) mice were treated with nab-P, mouse-specific nab-P (distribution experiments only), and solvent-based paclitaxel (pac-T). Blood and tissue samples were collected for distribution analyses. Organ, urine, and fecal samples were collected for elimination analyses. The nab-P tissue penetration in the pancreas, fat pad, and kidney of wild-type mice, as reflected by the ratio of tissue/plasma concentration, was significantly higher (ranging from 5 to 80 fold) than that of FcRn-KO mice. In contrast, the tissue penetration of pac-T in these organs of FcRn-KO mice was similar to that of wild-type mice. More importantly, the excretion of nab-P in feces of FcRn-KO mice (45–68%) was significantly higher than that of wild-type mice (26–46%) from 8 to 48 h post treatment. In comparison, the difference of excretion of pac-T in feces between FcRn-KO mice and wild-type mice was smaller than that of nab-P. Furthermore, greater tissue penetration and fecal excretion were observed with nab-P than pac-T in both FcRn-KO and wild-type mice. These findings suggest that FcRn enhances the tissue distribution and penetration of nab-P in the targeted organs, while FcRn prevents excretion of nab-P to feces in the intestinal lumen. The findings support the notion that albumin nanoparticle delivery alters drug distribution and elimination through an FcRn-mediated process to impact drug efficacy and toxicity.

Previous studies have shown that different paclitaxel formulations produce distinct anticancer efficacy and safety profiles in animals and humans. This study aimed to investigate the distinct pharmacokinetics and tissue distribution of various nanoformulations of paclitaxel, which may translate into potential differences in safety and efficacy. Four nanoparticle formulations (nab-paclitaxel, mouse albumin nab-paclitaxel [m-nab-paclitaxel], micellar paclitaxel, and polymeric nanoparticle paclitaxel) as well as solvent-based paclitaxel were intravenously administered to mice. Seventeen blood and tissue samples were collected at different time points. The total paclitaxel concentration in each tissue specimen was measured with liquid chromatography–tandem mass spectrometry. Compared with solvent-based paclitaxel, all four nanoformulations demonstrated decreased paclitaxel exposure in plasma. All nanoformulations were associated with paclitaxel blood-cell accumulation in mice; however, m-nab-paclitaxel was associated with the lowest accumulation. Five minutes after dosing, the total paclitaxel in the tissues and blood was approximately 44% to 57% of the administered dose of all paclitaxel formulations. Paclitaxel was primarily distributed to liver, muscle, intestine, kidney, skin, and bone. Compared with solvent-based paclitaxel, the different nanocarriers altered the distribution of paclitaxel in all tissues with distinct paclitaxel concentration–time profiles. nab-paclitaxel was associated with increased delivery efficiency of paclitaxel in the pancreas compared with the other formulations, consistent with the demonstrated efficacy of nab-paclitaxel in pancreatic cancer. All the nanoformulations led to high penetration in the lungs and fat pad, which potentially points to efficacy in lung and breast cancers. Micellar paclitaxel and polymeric nanoparticle paclitaxel were associated with high paclitaxel accumulation in the heart; thus, the risk of cardiovascular toxicity with these formulations may warrant further investigation. The solvent-based formulation was associated with the poorest paclitaxel penetration in all tissues and the lowest tissue-to-plasma ratio. The different nanocarriers of paclitaxel were associated with distinct pharmacokinetics and tissue distribution, which largely align with the observed efficacy and toxicity profiles in clinical trials.

ABSTRACTIntroduction: Ceftazidime-avibactam (CAZ-AVI) is a combination of a third-generation cephalosporin and a non-β-lactam, β-lactamase inhibitor, recently approved for urinary tract infections and complicated abdominal infections. Moreover, it represents a treatment option for patients with hospital acquired pneumonia (HAP), especially when caused by multidrug-resistant (MDR) bacteria.Areas covered: The review focuses on the pharmacokinetics (PK) of CAZ-AVI in HAP and on preclinical and clinical studies evaluating PK/pharmacodynamics (PD) in this field.Expert opinion: In vitroand in vivodata about PK/PD of CAZ-AVI confirm that penetration of CAZ-AVI in the epithelial lining fluid (ELF) represents approximately 30% of the plasma concentrations. Clinical studies documented that CAZ-AVI 2000 mg/500 mg every 8 h is the optimal dose regimen to achieve the PK/PD target attainment in patients with HAP. Thus, CAZ-AVI could represent an option both to treat HAP caused by Gram-negative bacilli (GNB) displaying resistance to most of the antibiotics and to reduce the use of carbapenems, limiting the onset of resistance profiles among GNB. Additional information about specific patients populations, such as critically-ill subjects or pediatric patients, are needed for a more individualized use of CAZ-AVI.

In vivodrug dissolution in the gastrointestinal (GI) tract is largely unmeasured. The purpose of this clinical study was to evaluate the in vivodrug dissolution and systemic absorption of the BCS class IIa drug ibuprofen under fed and fasted conditions by direct sampling of stomach and small intestinal luminal content. Expanding current knowledge of drug dissolution in vivowill help to establish physiologically relevant in vitromodels predictive of drug dissolution. A multilumen GI catheter was orally inserted into the GI tract of healthy human subjects. Subjects received a single oral dose of ibuprofen (800 mg tablet) with 250 mL of water under fasting and fed conditions. The GI catheter facilitated collection of GI fluid from the stomach, duodenum, and jejunum. Ibuprofen concentration in GI fluid supernatant and plasma was determined by LC–MS/MS. A total of 23 subjects completed the study, with 11 subjects returning for an additional study visit (a total of 34 completed study visits). The subjects were primarily white (61%) and male (65%) with an average age of 30 years. The subjects had a median [min, max] weight of 79 [52, 123] kg and body mass index of 25.7 [19.4, 37.7] kg/m2. Ibuprofen plasma levels were higher under fasted conditions and remained detectable for 28 h under both conditions. The AUC0–24and Cmaxwere lower in fed subjects vs fasted subjects, and Tmaxwas delayed in fed subjects vs fasted subjects. Ibuprofen was detected immediately after ingestion in the stomach under fasting and fed conditions until 7 h after dosing. Higher levels of ibuprofen were detected in the small intestine soon after dosing in fasted subjects compared to fed. In contrast to plasma drug concentration, overall gastric concentrations remained higher under fed conditions due to increased gastric pH vs fasting condition. The gastric pH increased to near neutrality after feedingbefore decreasing to acidic levels after 7 h. Induction of the fed state reduced systemic levels but increased gastric levels of ibuprofen, which suggest that slow gastric emptying and transit dominate the effect for plasma drug concentration. The finding of high levels of ibuprofen in stomach and small intestine 7 h post dosing was unexpected. Future work is needed to better understand the role of various GI parameters, such as motility and gastric emptying, on systemic ibuprofen levels in order to improve in vitropredictive models.

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ABSTRACTHigh doses of micafungin are advocated in neonates with systemic candidiasis, but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, three of whom had meningitis, were treated for at least 14 days with 8 to 15 mg/kg of body weight/day of intravenous micafungin. Plasma micafungin concentrations (four measurements for each patient) were determined after the third dose, and the cerebrospinal fluid (CSF) micafungin concentrations in three patients were also obtained. Population PK analyses were used to identify the optimal model, and the model was further validated using external data (n= 5). The safety of micafungin was assessed by measurement of the levels of liver and kidney function biomarkers. The mean age and weight at the initiation of treatment were 2.33 months (standard deviation [SD], 1.98 months) and 3.24 kg (SD, 1.61 kg), respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase concentration ratio. The CSF of three patients was sampled, and the observed concentrations were between 0.80 and 1.80 mg/liter. The model-predicted mean micafungin area under the concentration-time curve over 24 h was 336 mg · h/liter (SD, 165 mg · h/liter) with the 10-mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection, but 5 had neurologic impairments. Among the transaminases, alkaline phosphatase measurements were significantly higher posttreatment, with a geometric mean ratio of 1.17 (90% confidence interval, 1.01, 1.37). Furthermore, marked elevations in the gamma-glutamyltransferase (GGT) level were observed in three patients treated with 10- to 15-mg/kg/day doses, and improvement of the GGT level was noted after a dose reduction. Higher weight-based doses of micafungin were generally well tolerated in neonates and infants and achieved pharmacokinetic profiles predictive of an effect.

ABSTRACTTedizolid is a novel oxazolidinone antimicrobial administered in its prodrug form, tedizolid phosphate, as a fixed once-daily dose. The pharmacokinetics of tedizolid has been studied in a relatively small proportion of morbidly obese (body mass index [BMI] of ≥40 kg/m2) adults through population analyses with sparse sampling. The current study compared the intensively sampled plasma pharmacokinetics of tedizolid phosphate and tedizolid in 9 morbidly obese and 9 age-, sex-, and ideal body weight-matched nonobese (BMI, 18.5 to 29.9 kg/m2) healthy adult (18 to 50 years of age) volunteers after administration of a single intravenous dose of tedizolid phosphate. The median (range) weights were 72.6 kg (58.9 to 89.5 kg) and 117 kg (102 to 176 kg) for the mostly female (77.8%) nonobese and morbidly obese adults, respectively. Tedizolid phosphate concentrations were below the limit of quantitation in a majority of subjects after the 2-h time point. The tedizolid median (range) maximum concentration of drug in plasma (Cmax) and area under the concentration-time curve from 0 h to infinity (AUC0–∞) were 2.38 (1.28 to 3.99) mg/liter and 26.3 (18.4 to 43.2) h · mg/liter, respectively, for morbidly obese subjects, and these were nonsignificantly different (P≥ 0.214) from the values for nonobese subjects. Similarly, the volumes of distribution (Vz) (P= 0.110) and clearance (CL) values (P= 0.214) were comparable between groups. Nearly identical (P= 0.953) median tedizolid half-lives of approximately 12 h were observed for both groups. Tedizolid Vzand CL scaled with body weight, but not proportionately. The small and nonsignificant differences in tedizolid AUC0–∞values between morbidly obese and nonobese subjects suggest that dose modification is not necessary for morbidly obese adults. (This study has been registered at ClinicalTrials.gov under number NCT02342418.)

ABSTRACTThe pharmacokinetic profile of ceftaroline has not been well characterized in obese adults. The purpose of this study was to evaluate the pharmacokinetics of ceftaroline in 32 healthy adult volunteers aged 18 to 50 years in the normal, overweight, and obese body size ranges. Subjects were evenly assigned to 1 of 4 groups based on their body mass index (BMI) and total body weight (TBW) (ranges, 22.1 to 63.5 kg/m2and 50.1 to 179.5 kg, respectively). Subjects in the lower-TBW groups were matched by age, sex, race/ethnicity, and serum creatinine to the upper-BMI groups. Serial plasma and urine samples were collected over 12 h after the start of the infusion, and the concentrations of ceftaroline fosamil (prodrug), ceftaroline, and ceftaroline M-1 (inactive metabolite) were assayed. Noncompartmental and population pharmacokinetic analyses were used to evaluate the data. The mean plasma ceftaroline maximum concentration and area under the curve were ca. 30% lower in subjects with a BMI of ≥40 kg/m2compared to those <30 kg/m2. A five-compartment pharmacokinetic model with zero-order infusion and first-order elimination optimally described the plasma concentration-time profiles of the prodrug and ceftaroline. Estimated creatinine clearance (eCLCR) and TBW best explained ceftaroline clearance and volume of distribution, respectively. Although lower ceftaroline plasma concentrations were observed in obese subjects, Monte Carlo simulations suggest the probability of target attainment is ≥90% when the MIC is ≤1 μg/ml irrespective of TBW or eCLCR. No dosage adjustment for ceftaroline appears to be necessary based on TBW alone in adults with comparable eCLCR. Confirmation of these findings in infected obese patients is necessary to validate these findings in healthy volunteers. (This study has been registered at ClinicalTrials.gov under registration no. NCT01648127.)

Introduction:Intranasal insulin is a putative neuroprotective therapy that could be easily delivered very early after cardiac arrest, but safety at doses extrapolated from animal models have not been studied in humans. We hypothesized that high-dose intranasal insulin can be safely delivered to healthy human subjects.Methods:This was a phase 1, open label dose-finding study of intranasal insulin in healthy participants.The primary objective was to determine the maximum tolerated dose of intranasal insulin in healthy subjects. Placebo and insulin were given intranasally to supine healthy volunteers intranasally at escalating doses from 0 to 1000 units on repeated weekly visits. Serum glucose, insulin, and C-peptide levels were measured serially at 0, 15, 30, 60, 120, 180 and 240 minutes after administration.Results:Twenty four participants (12 female, median age 53.5, IQR 35.75-61) were enrolled. There was no change in average serum glucose after administration of intranasal insulin. Average serum insulin increased slightly in a dose-dependent manner, peaking at 15 minutes. C-peptide went down over time from administration in all groups. One participant had severe hypoglycemia (minimum 24 mg/dL 45 min after receiving 600U intranasal insulin) that was corrected with oral intake and intravenous dextrose. Another participant had transient hypoglycemia (minimum 51 mg/dL at 30 min) also after 600U intranasal insulin with mild symptoms that was corrected with oral intake. Hypoglycemic episodes were associated with increases in serum insulin. Both participants continued in the study without hypoglycemia after additional doses. One participant dropped out for reasons unrelated to the intervention.Discussion:High-dose intranasal insulin up to 1000U was well tolerated, without changes in mean glucose, but with small measurable systemic absorption. Idiosyncratic hypoglycemia requires further study. Delivery of intranasal insulin to the brain at these doses, and efficacy of high-dose intranasal insulin as a neuroprotective therapy after cardiac arrest require further study.

ABSTRACTRecent Food and Drug Administration (FDA) guidance endorses the use of an early clinical response endpoint as the primary outcome for community-acquired bacterial pneumonia (CABP) trials. While antibiotics will now be approved for CABP, in practice they will primarily be used to treat patients with community-acquired pneumonia (CAP). More importantly, it is unclear how achievement of the new FDA CABP early response endpoint translates into clinically applicable real-world outcomes for patients with CAP. To address this, a retrospective cohort study was conducted among adult patients who received ceftriaxone and azithromycin for CAP of Pneumonia Outcomes Research Team (PORT) risk class III and IV at an academic medical center. The clinical response was defined as clinical stability for 24 h with improvement in at least one pneumonia symptom and with no symptom worsening. A classification and regression tree (CART) was used to determine the delay in response time, measured in days, associated with the greatest risk of a prolonged hospital length of stay (LOS) and adverse outcomes (in-hospital mortality or 30-day CAP-related readmission). A total of 250 patients were included. On average, patients were discharged 2 days following the achievement of a clinical response. In the CART analysis, adverse clinical outcomes were higher among day 5 nonresponders than those who responded by day 5 (22.4% versus 6.9%, P= 0.001). The findings from this study indicate that time to clinical response, as defined by the recent FDA guidance, is a reasonable prognostic indictor of real-world effectiveness outcomes among hospitalized PORT risk class III and IV patients with CAP who received ceftriaxone and azithromycin.

ABSTRACTThe effects of several antimicrobial agents are predicted by the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC). Peak (Cp) and trough (Ct) concentrations are often measured clinically as surrogates of AUC because actual computation of AUC from 1 or 2 samples requires sophisticated mathematical methods. Given that the effects of daptomycin are predicted by AUC/MIC, our objective was to compare simple equation calculated AUC based on Cpand Ctto model integrated AUC. A standard population pharmacokinetic model was used to simulate 5,000 daptomycin concentration-time profiles after 5 doses of 6 mg/kg of body weight/day (0.5-h infusions). The AUC for the 24-h period was computed by integration and by equations with 110 Cp-Ctcombination pairs. The Cptime points were in 15-min increments between 0.5 h and 3 h and Ctin 15-min increments within an hour of the end of the dosing interval for each dose. The precision and bias of the calculated AUC relative to the integrated AUC were determined to identify Cp-Ctpairs associated with the lowest bias and highest precision. The equations were further validated using two daptomycin concentration-time data sets from healthy volunteers and critically ill patients. The precision and bias of calculated AUC were based primarily on Cp, and use of a daptomycin Cp1.5 h to 3 h from the start of infusion was associated with a bias of <10% and an R2of >0.95. Data from the healthy volunteers and critically ill patients also demonstrated declining bias with use of Cp≥1.5 h from the start of infusion with relatively good precision. Simplified equations using a daptomycin Cpapproximately 2 h from the start of infusion and a Ctwithin an hour of the end of the dosing interval should yield precise and unbiased estimates of daptomycin AUC.

ABSTRACTObese patients may be at a greater risk for acute kidney injury (AKI) with the use of certain antimicrobial agents that are dosed by weight. Current preclinical models of AKI utilize the male rat within a narrow weight range that limits extrapolation of the generated results. We evaluated the pharmacokinetics and AKI potential of gentamicin in 14-week-old diet-induced obesity-prone (n= 40) and obesity-resistant (n= 40) rats of both sexes. Single daily doses of gentamicin (12.5, 18.75, or 25 mg/kg of body weight) or saline (control) were administered intraperitoneally for 14 doses. Blood samples were collected after doses 1, 7, and 14, assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and analyzed using a nonparametric population pharmacokinetic approach for gentamicin. Urine was collected after doses 1, 3, and 5 and assayed for kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) and normalized to creatinine (Cr) values. Histology was performed on all animals, and the degree of proximal tubular injury was graded. The mean (minimum, maximum) weight of the rats was 330 (136, 580) g. NGAL/Cr predicted AKI better than did KIM-1/Cr and was detectable in male rats after dose 1 and in obesity-prone female rats after dose 5. Proximal tubular injury by histology was significantly higher in male than in female rats. A significant relationship between the gentamicin area under the curve from zero to 24 hours (AUC0–24) estimates and the maximum NGAL/Cr ratio was observed. This preclinical model has the potential to aid with dose extrapolation for body size and improve assessment of the toxicology potential of antimicrobials in development.

Background: Dosing adjustments for patients with impaired kidney function are often based on estimated creatinine clearance (eCrCI) because measuring kidney (unction is not always possible for dose adjustment. However, there is no consensus on the body size descriptor that should be used in the estimation equations.Objective: To compare the use of alternative body size descriptors (ABSDs) on the performance of kidney function estimation equations compared with measured CrCI (mCrCI).Methods: We combined 2 data sources with mCrCI: a Food and Drug Administration clinical trial database that includes subjects with body mass index (BMI) less than 40 kg/m2and published data from those 40 kg/m2or more. The 3 parent equations (Cockcroft-Gault [CG], Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease-Epidemiology Collaboration [CKDEPI]), and 14 ABSD-modilied equations were compared with mCrCI for accuracy, bias, agreement, goodness of (it (R2). and prediction error. These equations were also compared across mCrCI and BMI strata.Results: Subjects (n = 590) were aged 19–80 years; 33.9% were female and BMI ranged from 17.2 to 95.6 kg/m2. Compared with mCrCI, the use of total weight in the CG equation yielded low accuracy (12.5%) and significant bias (–107 mL/min) in the morbidly obese group. In contrast, the use of lean body weights (BMI ≥40 kg/m2) and total ± adjusted weights (BMI <40 kg/m2) with the CG equation yielded higher accuracy, greater than or equal to 60.7% across all BMI strata, and was unbiased. Transforming the MDRD or CKDEPI equations with body surface area improved accuracy only at mCrCI of 30–80 mL/min and increased the overall prediction error.Conclusions: No kidney function equation was consistently accurate and unbiased across weight, mCrCI. and estimate ranges. The accuracy and over-estimation bias of the CG equation in obese subjects was improved through the selective use of total, adjusted, and lean body weight by BMI strata.

ABSTRACTObesity is an independent risk factor for mortality in patients infected with pandemic influenza A virus (H1N1). Given the poor outcomes observed among adult obese patients with H1N1, the dosing of antiviral agents in this population has been questioned, and use of twice the standard oseltamivir dose has been suggested. However, studies evaluating the disposition of oseltamivir and oseltamivir carboxylate (the active metabolite) in the obese population are scant. We evaluated the single-dose and steady-state pharmacokinetics of oseltamivir (75 mg by mouth twice daily) in a cohort of 21 healthy adult volunteers with class III obesity (body mass index [BMI], ≥40 kg/m2). The median (minimum, maximum) age, weight, and BMI were 36 (19, 50) years, 122 (106, 159) kg, and 43.7 (40.0, 54.4) kg/m2, respectively. The population pharmacokinetic exposure profiles of oseltamivir carboxylate (the active metabolite) were comparable between class III obese subjects and nonobese adults (healthy and infected). Similar to previous pharmacokinetic analyses in nonobese subjects, the mean (percent covariance [CV]) area under the concentration-time curve for the dosing interval (AUC0–τ) was 2,621 ng·h/ml (17) for oseltamivir carboxylate. Body size was significantly (P< 0.05) associated with oseltamivir and oseltamivir carboxylate apparent clearance, but the correlation coefficient was poor (R2≤ 0.3). Creatinine clearance estimated by the Cockcroft-Gault method and lean body weight were also significantly (P< 0.05) but poorly (R2= 0.17) correlated with oseltamivir carboxylate apparent clearance. Since the systemic exposure of oseltamivir carboxylate is not reduced in class III obese adults with standard doses, a dose increment of oseltamivir is likely to be unnecessary.

ABSTRACTAminoglycosides are an important class of agents that are used in combination antimicrobial regimens to treat bacterial pathogens. Dosing of aminoglycosides is typically based on total body weight. However, the most appropriate alternative body size descriptor for dosing aminoglycosides at the extremes of weight (underweight and obese) is not known. Also, the predictive performance of newer formulas to assess kidney function, such as the modification of diet in renal disease (MDRD) and chronic kidney disease-epidemiology (CKD-EPI) equations compared to the Cockcroft-Gault equation to predict aminoglycoside clearance, is not known. We sought to examine dosing of aminoglycosides across the extremes of weight using a variety of formulas to assess kidney function. Pharmacokinetic data were obtained from a set of prospectively collected data (1982 to 2003) of 2,073 (53.5% male) adult patients that included 497 tobramycin- and 1,576 gentamicin-treated cases. The median (minimum, maximum) age, weight, and body mass index were 66 (18, 98) years, 70.0 (29.7, 206.7) kg, and 24.4 (11.3, 73.8) kg/m2, respectively. The percentage of underweight, normal-weight, overweight, and obese cases based on the World Health Organization classification were 8.8%, 45.5%, 26.5%, and 19.2%, respectively. The aminoglycoside volume of distribution was normalized to several alternative body size descriptors. Only lean body weight estimated by the method of S. Janmahasatian et al. (Clin. Pharmacokinet. 44:1051–1065, 2005) normalized the volume of distribution for both tobramycin and gentamicin across all weight strata, with the estimate being approximately 0.45 liter/kg. Aminoglycoside dosing can be simplified across all weight strata with the use of lean body weight. The CKD-EPI equation best predicts aminoglycoside clearance.

ABSTRACTWhile current data indicate only free (unbound) drug is pharmacologically active and is most predictive of response, pharmacodynamic studies of vancomycin have been limited to measurement of total concentrations. The protein binding of vancomycin is thought to be approximately 50%, but considerable variability surrounds this estimate. The present study sought to determine the extent of vancomycin protein binding, to identify factors that modulate its binding, and to create and validate a prediction tool to estimate the extent of protein binding based on individual clinical factors. This single-site prospective cohort study included hospitalized adult patients treated with vancomycin and with a vancomycin serum concentration determination available. Linear regression was used to predict the free vancomycin concentration (f[vanco]) and to determine the clinical factors modulating vancomycin protein binding. Among the 50 patients in the study, the mean protein binding was 41.5%. The strongest predictor of f[vanco] was the total vancomycin concentration (total [vanco]), and this was modified by dialysis and total protein of ≥6.7 g/dl as covariates. The algebraic expression from the final prediction model was f[vanco] = 0.643 + 0.560 × total [vanco] − {0.067 × total [vanco] × D} − {0.071 × total [vanco] × TP} where D = 1 if dialysis dependent or 0 if not dialysis dependent, and TP = 1 if total protein is ≥6.7 g/dl or 0 if total protein is <6.7 g/dl. The R2of the final prediction model was 0.959 (P< 0.001). Validation of our model was performed in 13 patients, and the predictive performance was highly favorable (R2was 0.9, and bias and precision were 0.18 and 0.18, respectively). Prediction models such as ours can be utilized in future pharmacokinetics and pharmacodynamics studies evaluating the exposure-response profile and to determine the pharmacodynamic target of interest as it relates to the free concentration.

Introduction:The prevalence of obesity and associated co-morbid conditions is increasing globally. Physiological changes accompanying obesity are likely to result in altered drug pharmacokinetics; however, there is paucity of information on how to best dose adjust for the obese.Areas covered:This review presents material describing physiological changes that occur in the obese and their relationship to body composition. The review also discusses various dosing metrics currently used to scale for size, and relationships between body composition and pharmacokinetic parameters. Through this, the reader is provided with a greater understanding of the key concepts regarding the physiological changes associated with obesity and how they relate to the changes in the pharmacokinetics.Expert opinion:There is a nonlinear relationship between total body weight and the physiological variables that determine drug clearance. Metrics that describe pharmacokinetics at the extremes of weight in a semi-mechanistic manner should be used as drug dosing scalars, with clinical trials adequately designed to correctly identify the most appropriate dosing scalar.

ABSTRACTVoriconazole is an antifungal agent that is currently used as primary therapy for invasive aspergillosis and as a potential treatment for systemic candidiasis. Data on the dosing of voriconazole in obese patients are not available, which is problematic given the increased prevalence of this special population. To address this limitation, we evaluated the steady-state plasma pharmacokinetics of voriconazole through a two-way, crossover design in a cohort of eight healthy volunteers with class II obesity or greater. The median (minimum, maximum) age, weight, and body mass index of obese subjects were 43 (22, 48) years, 133 (105, 155) kg, and 46.2 (38.4, 53.7) kg/m2, respectively. The geometric mean ratios (90% confidence intervals) for the area under the curve from time zero to 12 h (dosing interval; AUC0–τ), maximum concentration (Cmax), minimum concentration at 12 h (Cmin), and time to Cmax(Tmax) of the 300-mg to 200-mg dosing regimens were 2.0 (1.5, 2.7), 1.8 (1.4, 2.2), 2.2 (1.6, 2.9), and 1.6 (1.0, 2.4) in obese subjects, respectively. The AUC0–τvalues observed in obese subjects were comparable to those from a historical data set of nonobese subjects. Voriconazole dose-normalized AUC0–τvalues had a modestly better correlation with lean body weight (r2= 0.42) than total body weight (r2= 0.14). An excellent linear relationship (r2= 0.96) was identified between Cminvalues and AUC0–τvalues. Adjustment of voriconazole doses in individuals with class II obesity or greater does not appear to be necessary on the basis of body weight.

One-third of adult Americans are currently classified as obese. Physiologic changes associated with obesity can potentially alter the clearance of commonly used drugs. Clearance of certain drugs by the kidneys occurs primarily through glomerular filtration and tubular secretion. Obesity has been associated with glomerular hyperfiltration, whereas obesity-related effects on tubular secretion are not well characterized. Estimation of the glomerular filtration rate (GFR) is currently performed using serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. However, drug dosing guidelines are often based on creatinine clearance (CLcr) using the Cockcroft-Gault equation as a surrogate of GFR. There is a lack of consensus on the most appropriate method for estimation of GFR or CLcr in patients with obesity. The controversy relates to the use of 2 body size descriptors that confound these equations. The Cockcroft-Gault equation relies on total body weight and so overestimates GFR in patients with obesity. The MDRD equation indexes GFR based on a normalized body surface area, that is, mL/min/1.73 m2. Conversion of MDRD estimated GFR to non-normalized body surface area overestimates GFR in patients with obesity. The current review explores current approaches and controversies to estimation of GFR and CLcr among obese patients in clinical practice. The role of the alternate body size descriptor, lean body weight to estimate CLcr in obese patients is reviewed.

ABSTRACT5-Fluorocytosine (5FC) is an oral antifungal that is currently used in combination with amphotericin B to treat Cryptococcus neoformansmeningoencephalitis. The oral dosing of 5FC could be optimized by the use of a controlled-release (CR) formulation. The objective of the current study was to develop two prototype 5FC-CR formulations and evaluate the single-dose (1,500-mg) serum pharmacokinetic profiles of those formulations relative to the profile of the commercially available, immediate-release 5FC product (Ancobon) by the use of a phase 1, open-label, randomized, three-phase, crossover pharmacokinetic study design. Hydroxypropyl methylcellulose was utilized as the rate-controlling matrix to compound the 5FC-CR tablets. The two prototype 5FC-CR formulations demonstrated 80% release at 13.0 and 18.4 h, respectively, whereas the immediate-release product demonstrated 80% release at 0.28 h, as determined in vitroby the United States Pharmacopeia apparatus 2 dissolution method. Five subjects completed all three phases of the study without any adverse events. The mean maximum concentration, the area under the curve from time zero to 24 h, and the area under the curve from time zero to infinity were approximately 50% lower (P< 0.01) with the 5FC-CR formulations than with the immediate-release 5FC product. However, no statistically significant differences in the minimum concentrations at 24 h were noted between the formulations. The gastric absorption profile of 5FC-CR was well predicted by in vitrodissolution. Future exploration of a gastroretentive 5FC-CR formulation could overcome the marked lack of bioequivalence observed in the present study.

ABSTRACTIn vitro pharmacodynamic model (PDM) simulation of serum antifungal concentrations may predict the value of combination antifungal regimens against Candidasp. endocarditis. We investigated the effects of combinations of flucytosine (5FC), micafungin (Mica), and voriconazole (Vor) against Candida-infected human platelet-fibrin clots, used as simulated endocardial vegetations (SEVs). Single clinical bloodstream isolates of Candida albicans, Candida glabrata, Candida parapsilosis, and Candida tropicaliswere used. All four isolates were susceptible to 5FC, while C. glabratawas resistant to Vor and C. tropicalishad a paradoxical resistance phenotype to Mica. The SEVs were prepared with an initial inoculum of 1 × 106CFU/g of SEV and added to a PDM, which utilized yeast nitrogen broth-2% glucose and incubation at 35°C and simulated antifungal pharmacokinetic profiles. Fungal densities in the SEVs were determined in quadruplicate over 72 h. Scanning electron microscopy (SEM) was used to evaluate treatment and control SEVs. Vor was the least active single agent against all Candidaspp. except for C. parapsilosis, where it was comparable to Mica. In contrast, 5FC was the most active against all Candidaspp. except for C. tropicalis, where it was comparable to Mica. The combination of 5FC plus Vor was superior to either agent alone against C. parapsilosis. The combination of Vor plus Mica was inferior to the use of Mica alone against C. tropicalis. The triple combination of 5FC plus Vor plus Mica was no better than single or dual agents against any of the Candidaspp. The ultrastructural features of infected SEVs were unique for each Candidasp., with C. parapsilosisin particular manifesting friable biofilm clusters. In general, 5FC and Mica were superior in their rates and extents of fungal burden reduction compared to Vor against Candida-infected SEVs. Evaluation of 5FC and Mica in animal models of Candidaendocarditis is warranted.

ABSTRACTThe present study characterized the single-dose pharmacokinetics of daptomycin dosed as 4 mg/kg of total body weight (TBW) in seven morbidly obese and seven age-, sex-, race-, and serum creatinine-matched healthy subjects. The glomerular filtration rate (GFR) was measured for both groups following a single bolus injection of [125I]sodium iothalamate. Noncompartmental analysis was used to determine the pharmacokinetic parameters, and these values were normalized against TBW, ideal body weight (IBW), and fat-free weight (FFW) for comparison of the two groups. All subjects enrolled in this study were female, and the mean (±standard deviation) body mass index was 46.2 ± 5.5 kg/m2or 21.8 ± 1.9 kg/m2for the morbidly obese or normal-weight group, respectively. The maximum plasma concentration and area under the concentration-time curve from dosing to 24 h were approximately 60% higher (P< 0.05) in the morbidly obese group than in the normal-weight group, and these were a function of the higher total dose received in the morbidly obese group. No differences in daptomycin volume of distribution (V), total clearance, renal clearance, or protein binding were noted between the two groups. Of TBW, FFW, or IBW, TBW provided the best correlation to V. In contrast, TBW overestimated GFR through creatinine clearance calculations using the Cockcroft-Gault equation. Use of IBW in the Cockcroft-Gault equation or use of the four-variable modification of diet in renal disease equation best estimated GFR in morbidly obese subjects. Further studies of daptomycin pharmacokinetics in morbidly obese patients with acute bacterial infections and impaired renal function are necessary to better predict appropriate dosage intervals.

ABSTRACTThe present study tested in vitro susceptibility of Candidabloodstream isolates to fluconazole to determine if the ratio of the fluconazole area under the concentration-time curve (AUC) or weight-normalized daily dose (dosewn) to MIC correlated with mortality. Fluconazole susceptibility and outcome data were determined for 77 patients with a positive Candidablood culture between 2002 and 2005. The most commonly isolated Candidaspecies were C. albicans(64%), C. glabrata(14%), C. parapsilosis(8%), C. tropicalis(6%), and C. lusitaniae(4%). Only two isolates were classified as fluconazole resistant by the CLSI M27-A2 method. Fluconazole MICs were highest against C. glabratarelative to other Candidaspecies. Overall the crude mortality assessed at hospital discharge was 19.4% (n= 15). Mortality rates by species were as follows: C. albicans, 16.3%; C. glabrata, 36.4%; C. parapsilosis, 0%; C. tropicalis, 0%; C. lusitaniae, 33.3%. A mortality rate of 50% was noted among patients infected with nonsusceptible isolates (MIC ≥ 16 μg/ml) compared to 18% for patients infected with susceptible (MIC ≤ 8 μg/ml) isolates (P= 0.17). The fluconazole dosewn/MIC (24-h) values were significantly higher for the 62 survivors (13.3 ± 10.5 [mean ± standard deviation]) compared to the 15 nonsurvivors (7.0 ± 8.0) (P= 0.03). The fluconazole AUC/MIC (24 h) values also trended higher for survivors (775 ± 739) compared to nonsurvivors (589 ± 715) (P= 0.09). These data support the dose-dependent properties of fluconazole. Underdosing fluconazole against less-susceptible Candidaisolates has the potential to increase the risk of mortality associated with candidemia.

Infections with gram-positive organisms are highly prevalent in hemodialysis patients and are a major cause of morbidity and mortality in this population. Antimicrobial therapy is widely used to treat these infections, and prolonged therapy with these agents is often necessary. Extensive use of antimicrobials in hemodialysis patients has resulted in a growing threat of resistance, especially among gram-positive bacteria such as Enterococcusspp and Staphylococcus aureus. Vancomycin-resistant enterococci and S. aureusisolates with reduced susceptibility to vancomycin are increasingly being reported in hemodialysis patients. Additionally, resistance of these organisms to newer agents, such as linezolid and daptomycin, has been documented. Appropriate utilization of antimicrobial therapy to treat these organisms requires an understanding of the pharmacokinetic and pharmacodynamic principles to optimize therapy and avoid adverse drug events. The pharmacokinetic and pharmacodynamic profile of antimicrobial agents can be significantly altered in patients with chronic kidney disease. This review will describe mechanisms of antimicrobial resistance among common gram-positive organisms. The pharmacokinetic and pharmacodynamic principles of cephalosporins, vancomycin, aminoglycosides, linezolid, and daptomycin and applications for use of these agents in the treatment of patients with bloodstream infections on hemodialysis are discussed.

Objective: To report a case in which vancomycin clearance was used to determine the daptomycin dosing interval in a morbidly obese patient with renal impairment.Case Summary: A 46-year-old man (209 kg; 178 cm) failed a 42 day course of vancomycin therapy for treatment of a methicillin-resistant Staphylococcus aureus–infected wound and cellulitis. The median trough vancomycin concentration was 12.6 μg/mL (range 7.3–24.1) through his course of therapy. Estimation of creatinine clearance (Clcr) was confounded in this clinical scenario, given the patient's weight and a lack of valid equations in this patient population. Daptomycin was administered empirically at 6 mg/kg dosed every 48 hours based on estimated clearance from measured vancomycin concentrations. Steady-state plasma concentrations of daptomycin were determined, and the daptomycin half-life in this patient was more accurately estimated using vancomycin clearance as a surrogate. In addition, a 4 mg/kg dose of daptomycin would have been sufficient based on plasma concentrations. The patient demonstrated rapid clinical improvement and remained free of cellulitis for 6 months after completion of daptomycin and a 12 week course of trimethoprim/sulfamethoxazole.Discussion: The dosing interval of daptomycin is adjusted based on Clcr. However, estimation of Clcr is difficult in morbidly obese patients with renal impairment, given a lack of valid equations. In this clinical scenario, vancomycin concentrations were used to estimate Clcr and served as a surrogate measure to determine the daptomycin dosing interval. Measured daptomycin concentrations validated this approach and confirmed the inadequacy of commonly used Clcr equations.Conclusions: In this clinical scenario, vancomycin concentrations more accurately estimated Clcr, thereby facilitating determination of the daptomycin dosing interval.

Background: Vancomycin is frequently used to manage serious resistant gram-positive Infections. Neutropenia, whose epidemiology has not been well characterized, is a potentially serious adverse event associated with the use of vancomycin.Objective: To characterize the incidence and risk factors for development of vancomycin-induced neutropenia in patients treated with home intravenous vancomycin therapy.Methods: A retrospective chart review was conducted of adult patients receiving vancomycin therapy through the University of New Mexico Home Intravenous Infusion Clinic between January 1998 and December 2004. Data collection included demographics, comorbid conditions, dose and duration of vancomycin therapy, indications for vancomycin use, vancomycin concentrations, all concurrent medications, laboratory data, culture and susceptibility data, reasons for antibiotic alteration or discontinuations, all other recorded adverse events, management of adverse events, and outcomes of adverse events.Results: A total of 372 charts of patients managed through the clinic were reviewed and 114 patients treated with vancomycin were identified. Fourteen (12%) cases of vancomycin-induced neutropenia were identified; 4 (3.5%) cases included a reduction in absolute neutrophil count to 500 cells/mm3or less. The mean ± SD duration of vancomycin therapy and time to neutropenia were 32 ± 29 and 26 ± 15 days, respectively. Laboratory monitoring was performed on a weekly basis and resolution of vancomycin-induced neutropenia occurred promptly after discontinuation. Total vancomycin doses used and serum concentrations were not associated with the development of neutropenia.Conclusions: Vancomycin-induced neutropenia may occur at a higher frequency than previously reported. Clinicians should monitor hematologic parameters at least weekly in patients receiving home intravenous vancomycin therapy.

ABSTRACTThe present study assessed potential subclinical markers of amphotericin B (AmB)-related nephrotoxicity and infusion-related reactions (IRR). Subjects were pretreated with diphenhydramine and acetaminophen and received a 500-ml bolus infusion of 0.9% sodium chloride prior to each effective renal plasma flow (ERPF) assessment. ERPF was measured before and after administration of a single 0.25-mg/kg intravenous AmB dose using technetium-99m mercaptoacetyltriglycine. Blood was collected before and 3 h after AmB infusion for tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) plasma concentrations. Overnight 12-h urine collections were performed before administration of AmB and for 2 nights after administration of AmB and analyzed for α and π glutathione-S-transferases (GSTα and GSTπ, respectively) and N-acetyl-β-d-glucosaminidase (NAG). Six men and six women with mean ± standard deviation (SD) ages of 24.8 ± 5.3 and 28.0 ± 8.5 years, respectively, were studied. Baseline serum creatinine values were within the normal range and were unaltered after administration of AmB. The mean ± SD decrease in ERPF after administration of AmB was significant (P< 0.05) in males (15.7 ± 8.1%) but not females (9.5 ± 14.0%). The GSTπ and GSTα indices increased significantly (P< 0.05) by two to fourfold and returned to baseline in males but were unaltered in females. NAG indices were unaffected by AmB. Six patients experienced an IRR that was associated with increased TNF-α (P< 0.05) but not IL-1β (P= 0.09). These results suggest a potential sex-related difference in AmB-induced nephrotoxicity and provide a rationale for use of ERPF, urine GST, and TNF-α as subclinical markers of polyene-induced toxicity.

OBJECTIVE To evaluate the role of granulocyte colony-stimulating factor (G-CSF) as adjunctive therapy for the treatment of diabetic foot infections in non-neutropenic patients.DATA SOURCES Clinical literature was accessed through MEDLINE (1965–April 2004). Key search terms included G-CSF, infection, and diabetes. In addition, relevant references from primary and secondary article bibliographies were extracted.DATA SYNTHESIS Three clinical trials evaluating G-CSF for diabetic foot infections were identified. These data demonstrated positive effects of G-CSF on improvement of foot infections and risk of amputations.CONCLUSIONS Controlled trials are necessary to validate the role of adjunctive G-CSF at reducing amputations in patients with diabetic foot infections.

BACKGROUND: Gram-positive osteomyelitis requires long-term antibiotic therapy, much of which is often administered in the outpatient setting. Historically, synergistic aminoglycoside use in these infections requires multiple daily doses, which can be inconvenient. Data regarding extended-interval aminoglycoside dosing (EIAD), also known as once-daily dosing, in this setting are lacking.OBJECTIVE: To evaluate the safety and efficacy of EIAD in the treatment of gram-positive osteomyelitis.METHODS: Retrospective chart review of adult patients treated for documented, gram-positive osteomyelitis with EIAD at the University of New Mexico Home IV Antibiotic Clinic was conducted. The patients' medical records were reviewed by an infectious diseases clinical pharmacist. Clinical and microbiologic outcomes and the incidence of nephrotoxicity and ototoxicity were the main outcome measures.RESULTS: Fifteen patients (16 events) were included. Enterococcusspp. was the most common organism isolated. Nine patients had infected equipment or devices; 6 of these had removal of these devices in conjunction with antibiotic therapy. The median duration of antibiotic therapy was 6 weeks (range 6–31). The median duration of aminoglycoside therapy was 28 days (range 6–43). Seven patients developed nephrotoxicity, 5 of whom received an aminoglycoside in combination with vancomycin. Male patients had a higher risk of developing nephrotoxicity compared with females (p = 0.04). The mean ± SD duration of EIAD before the development of nephrotoxicity was 34 ± 8 days. Clinical cure was achieved in 12 (75%) patients. Three patients achieved clinical cure without hardware removal.CONCLUSIONS: Most of the patients with gram-positive osteomyelitis were successfully managed with EIAD. However, nephrotoxicity developed in a high proportion of patients and was likely related to prolonged aminoglycoside use.

BACKGROUND: An assessment of antifungal susceptibility testing (AST) has not been conducted since the introduction of the National Committee for Clinical Laboratory Standards (NCCLS) M27-A document.OBJECTIVE: To determine AST practices in teaching hospitals.METHODS: A questionnaire was mailed to the heads of 386 randomly assigned microbiology departments from teaching hospitals identified through the 2000 American Hospital Association Guide. Identifiers were used to delineate responders from nonresponders. A reminder letter was mailed 3 weeks after the initial mailing to all nonresponders. The hospital bed-size and number of inpatient days for respondents were obtained through the American Hospital Directory.RESULTS: The questionnaire was returned by 171 (44.3%) institutions. The total and median (range) number of candida isolates were 137 088 and 8.5 (1–145)/1000 inpatient days for the year 2000, respectively. Approximately 1% (1300) of candida isolates, from predominantly blood specimens, underwent AST. AST was reported by 115 (67.2%) hospitals, with testing on site at 27 hospitals and off site for 88 hospitals. NCCLS methodology (80% broth microdilution) was used by 75% of the hospitals performing on-site AST. The median time to obtain AST results was significantly lower when testing was performed on site (3 d) compared with off site (7–10 d).SUMMARY: A large number of candida bloodstream isolates undergoes AST annually. AST results are obtained sooner when performed on site compared with off site.

Fungal infections have been increasing at an alarming rate in critically ill patients.Candida is now the fourth most common pathogen isolated from the bloodstream and is associated with significant morbidity, mortality, and economic consequences. Novel antifungals have been developed in recent years to provide alternatives to amphotericin B, which continues to be the standard therapy for most invasive fungal infections. These alternatives include lipid-based amphotericin B, ketoconazole, fluconazole, itraconazole, caspofungin, and potentially voriconazole. Optimal therapy for the various forms of candidiasis remains controversial. A standardized antifungal susceptibility testing method for Candida isolates has been developed to assist drug selection, but its clinical relevance remains to be determined. The relative susceptibility ofCandida isolates can be estimated by the species. Specifically, C krusei is resistant to azoles, C glabrata may be resistant to azoles, andC lusitaniae may be resistant to amphotericinB Candida infections can affect any organ system, and the diagnosis of such infections remains difficult. The Infectious Diseases Society of America recently developed guidelines for the management of candidiasis. This review includes a brief discussion of systemically administered antifungal agents and provides a synopsis of the practice guidelines for the management of candidiasis.

OBJECTIVE: To review the literature regarding the prevention of catheter colonization and catheter-related bloodstream infections (CRBIs) with the use of antimicrobial-coated/bonded and -impregnated intravascular catheters.DATA SOURCES: Primary and review English-language literature were identified using MEDLINE (1966–September 2000) pertaining to the key terms antibiotic, antimicrobial, antiseptic, silver, and bonded, coated, impregnated catheters. In addition, textbooks and relevant reference lists were reviewed.DATA EXTRACTION: All articles identified through the data sources were evaluated. Information deemed relevant to the objectives of the review was included.DATA SYNTHESIS: Significant morbidity and mortality are associated with the development of CRBIs. Preventative measures such as modification of these catheters with antimicrobial coating/bonding have produced varying results. Trials evaluating cefazolin, teicoplanin, vancomycin, silver, and chlorhexidine—silver sulfadiazine (C-SS) used for coated/bonded intravascular catheters have not demonstrated a consistent decrease in the incidence of CRBIs. However, a meta-analysis of trials evaluating C-SS intravascular catheters demonstrated a statistically significant reduction in CRBIs. A larger reduction in CRBIs has been reported with minocycline—rifampin (M-R) versus C-SS intravascular catheters. Use of the M-R and C-SS catheters may result in a cost savings of $100 million and reduce as many as 12 000 CRBI-related deaths annually when used short term (<7 d).CONCLUSIONS: When used for short-term catheterization, M-R catheters appear to be superior to the currently available C-SS catheters at preventing CRBIs. Significant cost savings and reduction in mortality can be anticipated with the use of M-R catheters.

OBJECTIVE: To provide a historical perspective on the origin and similarity of the “ideal” body weight (IBW) equations, and clarify the terms ideal and lean body weight (LBW).DATA SOURCES: Primary and review literature were identified using MEDLINE (1966–November 1999) and International Pharmaceutical Abstracts (1970–November 1999) pertaining to ideal and lean weight, height–weight tables, and obesity. In addition, textbooks and relevant reference lists were reviewed.DATA EXTRACTION: All articles identified through the data sources were evaluated. Information deemed to be relevant to the objectives of the review were included.DATA SYNTHESIS: Height–weight tables were generated to provide a means of comparing a population with respect to their relative weight. The weight data were found to correlate with mortality and resulted in the use of the terms desirable or ideal to describe these weights. Over the years, IBW was interpreted to represent a “fat-free” weight and thus was used as a surrogate for LBW. In addition, the pharmacokinetics of certain drugs were found to correlate with IBW and resulted in the use of IBW equations published by Devine. These equations were consistent with an old rule that was developed from height–weight tables to estimate IBW. Efforts to improve the IBW equations through regression analyses of height–weight data resulted in equations similar to those published by Devine.CONCLUSIONS: The similarity between the IBW equations was a result of the general agreement among the various height–weight tables from which they were derived. Therefore, any one of these equations may be used to estimate IBW.

OBJECTIVE: To describe the current drug interaction profiles for the commonly used macrolides in the US and Europe, and to comment on the clinical impact of these interactions.DATA SOURCES: A MEDLINE search (1975–1998) was performed to identify all pertinent studies, review articles, and case reports. When appropriate information was not available in the literature, data were obtained from the product manufacturers.STUDY SELECTION: All available data were reviewed to provide an unbiased account of possible drug interactions.DATA EXTRACTION: Data for some of the interactions were not available from the literature, but were available from abstracts or company-supplied materials. Although the data were not always explicit, the best attempt was made to deliver pertinent information that clinical practitioners would need to formulate practice opinions. When more in-depth information was supplied in the form of a review or study report, a thorough explanation of pertinent methodology was supplied.DATA SYNTHESIS: Several clinically significant drug interactions have been identified since the approval of erythromycin. These interactions usually were related to the inhibition of the cytochrome P450 enzyme systems, which are responsible for the metabolism of many drugs. The decreased metabolism by the macrolides has in some instances resulted in potentially severe adverse events. The development and marketing of newer macrolides are hoped to improve the drug interaction profile associated with this class. However, this has produced variable success. Some of the newer macrolides demonstrated an interaction profile similar to that of erythromycin; others have shown improved profiles. The most success in avoiding drug interactions related to the inhibition of cytochrome P450 has been through the development of the azalide subclass, of which azithromycin is the first and only to be marketed. Azithromycin has not been demonstrated to inhibit the cytochrome P450 system in studies using a human liver microsome model, and to date has produced none of the classic drug interactions characteristic of the macrolides.CONCLUSIONS: Most of the available data regarding macrolide drug interactions are from studies in healthy volunteers and case reports. These data suggest that clarithromycin appears to have an interaction profile similar to that of erythromycin. Given this similarity, it is important to consider the interaction profile of clarithromycin when using erythromycin. This is especially necessary as funds for further studies of a medication available in generic form (e.g., erythromycin) are limited. Azithromycin has produced few clinically significant interactions with any agent cleared through the cytochrome P450 enzyme system. Although the available data are promising, the final test should come from studies conducted in patients who are taking potentially interacting compounds on a chronic basis.

ABSTRACTWe report on the pharmacokinetics (PK) and pharmacodynamics (PD) of high-dose (>15 mg/kg of body weight per day) amikacin. A mean (standard deviation [SD]) maximum drug concentration in the serum (Cmax) and 24-h area under the concentration-time curve (AUC24) of 101 (49.4) mg/liter and 600 (387) mg · h/liter, respectively, were observed (n= 73) with 28.0 (8.47) mg/kg/day doses. An initial amikacin dose of 2,500 mg in adults weighing 40 kg to 200 kg with therapeutic drug monitoring to adjust the maintenance dose will optimize its PK and PD.

ABSTRACTPharmaceutical differences between the reference listed drug (RLD) and generic formulations of piperacillin-tazobactam may impact the reconstitution process for intravenous administration. This study evaluated the RLD against three generic formulations and measured their reconstitution times using a standardized process. The mean (standard deviation [SD]) reconstitution time for one generic formulation was 5.57 (1.49) min, which was 35% to 42% longer (P< 0.002) than that for the RLD and two other formulations. Observable microscopic differences in powder particle morphology may explain these findings.

ABSTRACTThe serum pharmacokinetic profile of intravenous (i.v.) tobramycin administration was characterized for a sample of nine adult patients with cystic fibrosis (CF) who were hospitalized for an acute pulmonary exacerbation. Current recommended i.v. tobramycin dosing protocols are predicted through modeling and simulation to be suboptimal. Empirical tobramycin regimens of ≥15 mg/kg of body weight administered i.v. once daily should be evaluated for adult patients with CF to optimize outcomes.

ABSTRACTThe in vitro effects of flucytosine (5FC), liposomal amphotericin B (L-AmB), and micafungin (Mica) combinations against two Candida albicansstrains that simulated 24-hour-old endocardial vegetations were studied. Mica was superior to 5FC or L-AmB, and the 5FC-L-AmB-Mica combination was superior to all other treatments for one strain but no different from the dual combination of L-AmB-Mica for the other strain.

Limited data are available on the most appropriate dosing, efficacy, and safety of micafungin in neonates with invasive candidiasis (IC). This study evaluated plasma levels, efficacy, and safety of micafungin at a dose of 8 mg/kg daily for a mean of 13.3 days (±5.2 days) in 35 neonates and young infants with IC.

The risk of vancomycin (VAN)-associated acute kidney injury (AKI) may be altered with combination regimens. The specific AKI risk when VAN is combined with imipenem-cilastatin/relebactam (IMP-C/REL) or piperacillin/tazobactam (TZP) has not been clearly defined.

In patients with renal impairment (n= 22 of 39), the median serum concentrations of linezolid, PNU-142300, and PNU-142586 were 1.6-, 3.3-, 2.8-fold higher, respectively, than in patients without renal impairment. Metabolite concentrations in paired samples were poorly correlated with linezolid concentrations (r2= 0.26 for PNU-142300 and 0.06 for PNU-142586). Linezolid and its metabolites share potential toxicophores that deserve characterization to mitigate higher myelosuppression risk in patients with renal impairment.

ABSTRACTWe studied the MICs of triazoles against 15 Candida glabrataclinical isolates by the NCCLS M27-A2, Sensititre YeastOne, and Etest methods by using media at pHs 6.0, 7.0, and 7.4. Thirteen isolates were less susceptible to triazoles at pH 6.0 and more susceptible to triazoles at pH 7.4 compared to pH 7.0.