Fruit and vegetable intake and bone health in women aged 45 years and over: a systematic review.

UNLABELLED: High fruit and vegetable intake may be associated with improved bone status among women aged ≥ 45 years. This is the first systematic review that specifically assessed this association and identified research gaps. The benefits of fruit and vegetables (F&V) on bone health remain unclear. Further studies are needed. INTRODUCTION: F&V have several components that are beneficial to bones. Some studies report that high F&V intake is associated with improved bone status in middle aged and aged women; however, findings are inconsistent. The objective was to systematically review observational and interventional studies that investigated the effects of F&V intake on incidence of osteoporotic fractures, bone mineral density (BMD), and bone turnover markers (BTM) in women aged ≥ 45 years and to identify potential research gaps. METHODS: Electronic databases were searched, and peer-reviewed manuscripts published in English, with F&V intake as a main dietary exposure, were included. Data selection, extraction, and evaluation of risk of bias were performed independently by two reviewers. RESULTS: Eight studies were included. One cohort study reported cross-sectional as well as longitudinal data. There was significant between-study heterogeneity in design, definition, and amount of F&V intake, outcomes, analyses, and reporting of results. Two studies had low, two had moderate, and four had high risk of bias. Among reports with low or moderate risk of bias, two cross-sectional analyses reported positive associations between F&V intake and BMD of the forearm, lumbar spine, or total hip, whereas one randomized controlled trial and two prospective cohort analyses reported no effects. One trial reported no associations between F&V and BTM. CONCLUSIONS: Based on limited evidence, the benefits of F&V on bone health remain unclear for women aged ≥ 45 years. Further studies with low risk of bias are needed.

Ventilator associated pneumonia caused by Raoultella ornithinolytica in two immunocompetent trauma patients.

Infections with Raoultella ornithinolytica have recently been reported more frequently in the medical literature. This pathogen has the potential to cause many types of infections, including pneumonia. Here, we report the first two cases of ventilator-associated pneumonia (VAP) in trauma patients caused by Raoultella ornithinolytica. Both of these infections were successfully treated with antibiotics based on susceptibilities and the patients were able to be transferred out of the intensive care unit.

Imipenem pharmacokinetics in patients with burns.

The pharmacokinetics of imipenem were studied in 11 adult patients with severe burns who were receiving a therapeutic regimen of imipenem-cilastatin 500 mg intravenously every 6 hours. Serial blood samples for measuring imipenem and 24-hour urine collections for creatinine clearance (CrCl) were obtained after the initial dose and after multiple dosing. Plasma was assayed for imipenem by use of HPLC. A two-compartment model provided a superior fit to the data compared with a one-compartment model in 9 of the 11 patients. There was no significant difference in any pharmacokinetic parameter between the initial dose and after multiple dosing (p greater than 0.05). Combined mean (+/- SD) parameter estimates for the two dosing periods were as follows: VC, 0.11 +/- 0.06 L/kg; Vss, 0.22 +/- 0.06 L/kg; CL, 12.5 +/- 3.6 L/hr/1.73 m2; t1/2 alpha, 0.18 +/- 0.13 hr; t1/2 beta, 1.12 +/- 0.44 hr. Mean clearance in two patients with creatinine clearance values greater than 150 ml/min/1.73 m2 was 17.7 L/hr/1.73 m2. Mean clearance in two patients with creatinine clearance values less than 50 ml/min/1.73 m2 was 8.5 L/hr/1.73 m2. No pharmacokinetic parameter was significantly different from previously reported parameters in normal volunteers (p greater than 0.05). Creatinine clearance ranged from 17 to 218 ml/min/1.73 m2. Imipenem clearance was significantly related to creatinine clearance (CL = 63 + 0.059 CLCR; r2 = 0.60, p = 0.001). No significant association was found between total body surface area burns and imipenem clearance (p greater than 0.05). Our data suggest imipenem pharmacokinetics in patients with burns are comparable to those in normal volunteers although substantial intersubject variability exists.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of neurotrauma on hepatic drug clearance.

Lorazepam, antipyrine, and indocyanine green were administered to 10 patients with severe head injuries as marker substrates of hepatic glucuronidation, oxidation, and hepatic blood flow, respectively. Pharmacokinetic parameter estimates were determined at baseline (20 to 80 hours after injury) and up to three additional times thereafter (study days 4, 7, and 14). Antipyrine clearance was increased significantly from baseline (0.50 +/- 0.31 ml/min/kg) on study days 4, 7, and 14 (p less than 0.0001). Increases in antipyrine clearance from baseline to the last study day were observed in all study patients ranging from 14% to 207%. A significant increase was also observed in lorazepam clearance on study day 14 relative to baseline (1.39 +/- 0.56 ml/min/kg) (p less than 0.005). Increases in lorazepam clearance occurred in seven of nine patients over time ranging from 9% to 130%. The unbound fraction of lorazepam did not change significantly over the study period. Likewise, no significant change was observed in the clearance of indocyanine green over time. Antipyrine clearance and alpha 1-acid glycoprotein (r = 0.41), and lorazepam clearance and C-reactive protein (r = -0.38) were significantly correlated (p less than 0.05). Similarly, antipyrine and lorazepam clearances were significantly correlated with injury severity based on the Acute Physiologic and Chronic Health Evaluation (APACHE II) score (r = -0.43 and r = -0.37, respectively). These findings suggest that hepatic oxidative and conjugative metabolism increase significantly over time in patients after acute head injury. An awareness of the potential for pharmacokinetic alterations in similarly metabolized drugs used for patients with severe head injuries is recommended.

Phenytoin pharmacokinetics in critically ill trauma patients.

Preliminary data have suggested that phenytoin systemic clearance may increase during initial therapy in critically ill patients. The objectives for this study were to model the time-variant phenytoin clearance and evaluate concomitant changes in protein binding and urinary metabolite elimination. Phenytoin was given as an intravenous loading dose of 15 mg/kg followed by an initial maintenance dose of 6 mg/kg/day in 10 adult critically ill trauma patients. Phenytoin bound and unbound plasma concentrations were determined in 10 patients and urinary excretion of the metabolite p-hydroxyphenyl phenylhydantoin (p-HPPH) was measured in seven patients for 7 to 14 days. A Michaelis-Menten one-compartment model incorporating a time-variant maximal velocity (Vmax) was sufficient to describe the data and superior to a conventional time-invariant Michaelis-Menten model. Vmax for the time-variant model was defined as V'max + Vmax delta (1 - e(-kindt)). Vmax infinity is the value for Vmax when t is large. The median values (ranges) for the parameters were Km = 4.8 (2.6 to 20) mg/L, Vmax infinity = 1348 (372 to 4741) mg/day, and kind = 0.0115 (0.0045 to 0.132) hr-1. Phenytoin free fraction increased in a majority of patients during the study period, with a binding ratio inversely related to albumin. Measured urinary p-HPPH data were consistent with the proposed model. A loading and constant maintenance dose of phenytoin frequently yielded a substantial, clinically significant fall in plasma concentrations with a pattern of apparently increasing clearance that may be a consequence of changes in protein binding, induction of metabolism, or the influence of stress on hepatic metabolic capacity.

Pharmacokinetics and safety of a phenytoin prodrug given i.v. or i.m. in patients.

ACC-9653, a prodrug of phenytoin synthesized to be water soluble, is converted to phenytoin by phosphatases. In this study, 43 patients received ACC-9653 IV or IM. Side effects were transient and minor. The conversion half-lives of ACC-9653 after intravenous and intramuscular administration averaged 8.4 and 32.7 minutes, respectively. Peak phenytoin concentrations occurred 42 minutes after IV and 151 minutes after IM administration.

Pharmacokinetic alterations after severe head injury. Clinical relevance.

Pharmacological therapy, present and future, will undoubtedly continue to play a large role within the overall management of patients with severe head injury. Nevertheless, limited clinical data are available to evaluate the effect of severe head injury on pharmacokinetics. The disruption of the blood-brain barrier secondary to trauma and/or subsequent hyperosmolar therapy can be expected to result in higher than expected brain drug concentrations. Aggressive dietary protein supplementation may result in increased oxidative drug metabolism. These effects may counterbalance inhibitory influences on drug metabolism secondary to cytokine release during the acute phase response. Alterations in protein binding can also be anticipated with the hypoalbuminaemia and increases in alpha 1-acid glycoprotein typically observed in these patients. Based on studies in other patient populations, moderate hypothermia, a treatment strategy in patients with head injury, can decrease drug metabolism. The pharmacokinetics of the following drugs in patients with severe head injury have been studied: phenytoin, pentobarbital (pentobarbitone), thiopental (thiopentone), tirilazad, and the agents used as marker substrates, antipyrine, lorazepam and indocynanine green (ICG). Several studies have documented increase in metabolism over time with phenytoin, pentobarbital, thiopental, antipyrine and lorazepam. Increases in tirilazad clearance were also observed but attributed to concurrent phenytoin therapy. No changes in the pharmacokinetics of ICG were apparent following head injury. With the frequent use of potent inhibitors of drug metabolism (e.g., cimetidine, ciprofloxacin) the potential for drug interaction is high in patients with severe head injury. Additional pharmacokinetic investigations are recommended to optimise pharmacological outcomes in patients with severe head injury.

Use of selected visceral protein measurements in the comparison of branched-chain amino acids with standard amino acids in parenteral nutrition support of injured patients.

Twenty injured patients in the intensive care unit were randomized to receive parenteral nutrition with either 21% (STD) or 46% (HBC) branched-chain amino acids to compare the response of nitrogen balance (NB), somatomedin-C/insulin-like growth factor I (SMC), circulating fibronectin (FBN), and prealbumin (PA). NB was measured and serum collected for SMC, FBN, and PA on days 1, 4, 7, 14, and 21 of nutritional intervention. The treatment groups did not differ significantly for age, weight, injury severity score, trauma score, Apache II score, acute-phase protein concentrations, or type of injury. Comparison of baseline measurements revealed no significant differences in SMC, FBN, or PA. Both groups received similar doses of nonprotein energy and nitrogen. Baseline urea nitrogen excretion was slightly higher in the STD group (216 +/- 55 vs 268 +/- 54 mg/kg/day p = 0.049). Although NB was significantly improved over baseline during subsequent study days, there were no differences between groups after the day-1 measurement. SMC increased significantly from baseline on day 4 in the STD group, on day 7 in the HBC group, and on days 14 and 21 in both groups. There was no significant difference in SMC concentrations between groups on any day. Each group demonstrated a significant increase in PA from baseline on days 7, 14, and 21; however, no difference was seen when groups were compared. FBN increased significantly from baseline on day 14 in the HBC group and on days 7 and 14 in the STD group. FBN measurements were significantly different between groups on day 14 (STD, 179 +/- 71 vs HBC, 229 +/- 59 micrograms/ml; p less than 0.05). NB, PA, SMC, and FBN improve significantly during parenteral nutrition of traumatized patients. With the measured variables, there appears to be no significant difference between STD or HBC amino acids when used as part of parenteral nutrition in injured patients.

Antibiotic pharmacokinetics following fluid resuscitation from traumatic shock.

OBJECTIVE: To describe the pharmacokinetic profile of aztreonam and vancomycin hydrochloride in a clinically relevant experimental model of hemorrhagic shock and trauma. METHODS: Ten mongrel pigs (mean +/- SD weight, 26.7 +/- 6.4 kg) were anesthetized with fentanyl citrate and ventilated, and an indwelling catheter was placed in the jugular vein. On day 3, all pigs were subjected to fentanyl administration, ventilation, soft-tissue injury, and an arterial hemorrhage (mean +/- SD, 40% +/- 8%). After a 1-hour shock period, baseline hemodynamics were restored by reinfusing shed blood plus twice the shed volume as lactated Ringer's solution. Aztreonam and vancomycin were infused on day 1, after resuscitation on day 3, and on days 4 and 8. Serial plasma samples were collected for 6 hours after treatment, and differences were compared with analysis of variance. RESULTS: Aztreonam clearance initially decreased with trauma, but subsequently increased by 48% (P < .02) by day 8. Aztreonam steady-state volume decreased by 34% (P = .05, baseline value vs that on day 8). Vancomycin clearance was increased between 25% and 52% (P < .001) on days 3, 4, and 8 compared with the baseline value. Vancomycin steady-state volume initially increased with trauma (P = .009), but it subsequently decreased by 29% (P < .001) on day 8. These data cannot be explained by changes in plasma volume per se because levels of plasma sodium, potassium, chloride, and calcium were within normal reference ranges at all time points. Neither liver nor renal functions were severely impaired because levels of serum urea nitrogen, bilirubin, liver enzymes, creatinine, and plasma proteins were within normal reference ranges. Furthermore, our previous work demonstrated that systemic and splanchnic organ oxygen delivery and demand were near normal immediately after fluid resuscitation and for at least 3 days thereafter; thus, there were probably no major perfusion abnormalities in the liver or kidney. CONCLUSIONS: For at least 5 days after trauma, clearance and steady-state volume of aztreonam and vancomycin are altered. These changes suggest that the interval and magnitude of dosing should be adjusted, relative to the standard recommended dosages of each antibiotic, to maximize their efficacy. Similar studies should be done for other antibiotics.

Pneumonia and stress ulceration in severely injured patients. A prospective evaluation of the effects of stress ulcer prophylaxis.

Stress ulcer prophylaxis is a routine aspect of the care of critically injured patients. Recent reports have suggested that patients undergoing prophylaxis with histamine antagonists are predisposed to nosocomial pneumonia, and that treatment with sucralfate can prevent this problem. An open, prospective randomized trial of three regimens was conducted with 278 evaluable patients. The patients were assigned to one of three group: the group receiving sucralfate, the group receiving a cimetidine hydrochloride bolus, and the group undergoing continuous infusion with cimetidine. Stress ulceration developed in 8% of patients in the sucralfate group, 13% of patients in the cimetidine bolus group, and 12% of patients in the cimetidine infusion group, while nosocomial pneumonia developed in 29% of patients in the sucralfate group, 32% of patients in the cimetidine bolus group, and 23% of patients in the cimetidine infusion group. Multivariate analysis of risk factors associated with pneumonia demonstrated independent significance for score on the Glasgow Coma Scale, Injury Severity Score, cord injury, shock, and head injury. Only spinal cord injury was associated with stress ulceration. We conclude that sucralfate and cimetidine are both effective for stress ulcer prophylaxis and that there is no association of cimetidine with nosocomial pneumonia.

The acute effects of the enkephalin analogue BW 942C in humans.

BW 942C hydrochloride is an enkephalin analogue that has exhibited a wide separation between antidiarrheal dosages and dosages inducing adverse effects in animals. This has likewise been the case in humans when administered orally. In this study, the safety and tolerance of single 0.5-mg doses of intravenous BW 942C compared with placebo were assessed in humans. Four healthy male volunteers received BW 942C, and two received placebo. The effects of BW 942C on serum growth hormone (GH), luteinizing hormone (LH), prolactin (PR), and follicle-stimulating hormone (FSH) were assessed in three of these volunteers. No significant changes were apparent in vital signs, in clinical chemistry, hematologic and urine studies following BW 942C administration. BW 942C did not appear to alter mood as assessed by two psychologic mood scales. Prolactin levels tended to increase in volunteers receiving BW 942C two hours postinfusion. Luteinizing hormone concentrations decreased slightly at two and six hours. No trends in FSH or GH could be identified. Pulmonary function testing did not reveal any significant changes in oximetry, spirometry, or plethysmography in any of the subjects. A marked decrease in CO2 responsiveness in two subjects may indicate that BW 942C has mild ventilatory depressant effects. Untoward effects experienced in volunteers receiving BW 942C included heaviness in the limbs, nasal stuffiness, mouth dryness, facial flushing, skin rash, and prickling sensations. These effects bear a striking similarity to those experienced after parenteral administration of other enkephalin analogues. Intravenous administration of BW 942C up to 0.5 mg appears safe from a laboratory, physiologic, and clinical perspective with unusual untoward effects that may preclude rational use of the drug by the parenteral route.

Effect of acute phase response on phenytoin metabolism in neurotrauma patients.

The purpose of this prospective study was to correlate measures of the acute phase response, associated therapeutic interventions, and other clinical variables with the process of altered drug metabolism previously observed in patients with severe neurotrauma. Nine patients with severe head injury (Glasgow Coma Scale < or = 8) requiring intravenous phenytoin were included in the study. A loading dose of phenytoin was followed by daily maintenance doses. Serial blood samples were taken after the loading dose and every even-numbered study day for 10 to 14 days for measurement of total and unbound concentrations of phenytoin, interleukin-1 beta, interleukin-6 (IL-6), tumor necrosis factor alpha, alpha 1-acid-glycoprotein, C-reactive protein, and albumin. Time-invariant and time-variant Michaelis-Menten models were fit to the phenytoin concentration-time data. Protein intake was closely monitored. The mean (+/- SEM) unbound fraction of phenytoin increased from 0.17 +/- 0.02 on day 1 to 0.24 +/- 0.04 on day 10 (P < 0.05). The time-variant model was superior in describing the concentration-time data of unbound phenytoin in eight of nine patients. Mean (+/- SEM) pharmacokinetic parameter estimates for unbound phenytoin were: Vmax delta = 605 +/- 92 mg/day, VmaxB = 149 +/- 26.3 mg/day, K(ind) = 0.013 +/- 0.004 hr-1. Interleukin-6 was the only cytokine with significant concentration changes over time; it was inversely correlated with Vmax,t. Peak concentrations of interleukin-6 also proved to be inversely correlated with VmaxB. The daily amount of protein administered was significantly correlated with Vmax,t. Significant alterations in the metabolism of phenytoin occur after severe neurotrauma. The etiology of these changes is probably multifaceted. These results suggest that low initial phenytoin Vmax may be explained by the presence of interleukin-6. An increase in oxidative metabolism that correlated with nutritional protein administration was observed later in these patients.

Fosphenytoin: a novel phenytoin prodrug.

Fosphenytoin is a phenytoin prodrug that received an approvable letter from the Food and Drug Administration in February 1996. It was designed to overcome many of the shortcomings associated with parenteral phenytoin sodium. Specifically, fosphenytoin is a highly water-soluble, phosphate ester of phenytoin that has no known pharmacologic activity before its conversion to phenytoin. Dosing of fosphenytoin uses phenytoin equivalents (PE) to minimize dosage errors when converting from the conventional formulation. Pharmacokinetic studies documented that the agent is rapidly and completely converted to phenytoin after intravenous and intramuscular dosing. Reported conversion half-lives after intravenous administration range from 8-15 minutes. The absorption rate appears to be the rate-limiting step in the conversion of fosphenytoin to phenytoin after intramuscular administration (half-life range 22-41 min). Bioavailability of phenytoin derived from both intravenous and intramuscular fosphenytoin is essentially 100%. As a consequence of concentration-dependent protein binding, fosphenytoin is bioequivalent to phenytoin sodium at intravenous infusion rates of 100-150 mg PE/minute and 50 mg/minute, respectively. In clinical studies to date, fosphenytoin is safe and significantly better tolerated than phenytoin sodium when administered intravenously. It is also well tolerated when given intramuscularly, and this is a valuable alternative route of administration when intravenous access or cardiographic monitoring is unavailable. Its pharmacoeconomic advantages over phenytoin have not been documented in formal studies to date, although the likelihood of savings based on cost-effectiveness analyses is high. Hence, fosphenytoin has the potential as a safe, well-tolerated, and effective means of delivering phenytoin parenterally in a variety of clinical settings.

Aerosolized antimicrobial therapy in acutely ill patients.

Recent data are sparking renewed interest in therapy with aerosolized antimicrobials in critically ill patients as well as other populations such as those with neutropenia, human immunodeficiency virus infection, and cystic fibrosis. Pneumonia is a common complication in these patients and is associated with substantial morbidity and increased mortality. Clinical trials evaluated aerosolized antimicrobials for the prevention and treatment of pneumonia in hospitalized patients. In addition, factors that affect the pulmonary deposition of aerosolized drugs in mechanically ventilated patients were identified.

Hepatic drug metabolism in critical illness.

Hepatic drug metabolism is altered in critically ill patients. The etiology and mechanisms of the alterations are not clearly understood and are difficult to address in clinical studies. For this reason, in vitro and animal models were developed to investigate the effects of critical illness on hepatic drug metabolism. Specifically, those with sepsis, septic shock, hemorrhagic shock, trauma, neurotrauma, and burns are populations that have been studied. Most of this research, however, has not led to established guidelines for the administration of drugs in these populations.

Pharmacoeconomics of aztreonam-clindamycin versus gentamicin-clindamycin in the treatment of penetrating abdominal injury.

STUDY OBJECTIVE: To evaluate the pharmacoeconomic implications of using aztreonam-clindamycin (A-C) versus gentamicin-clindamycin (G-C) from the perspective of the hospital and pharmacy directors. DESIGN: Pharmacoeconomic analysis performed at one of the sites participating in the prospective, randomized, double-blind, comparative, multicenter efficacy study. SETTING: Referral hospital with level 1 trauma center. PATIENTS: Eight-five adults with a suspected penetrating intraabdominal injury requiring laparotomy. INTERVENTIONS: Patients were randomized to receive aztreonam 2 g intravenously every 8 hours or gentamicin 2 mg/kg intravenous load followed by 5 mg/kg/day intravenously initially adjusted to peak concentrations of 6-8 micrograms/ml. All patients received clindamycin 900 mg intravenously every 8 hours. MEASUREMENTS AND MAIN RESULTS: Charge data were gathered from the hospital billing system and converted to cost data using an institutional cost:charge ratio of 0.6. Study drug and aminoglycoside monitoring costs were also calculated. Overall, 43 (97%) of 44 patients receiving A-C had a favorable clinical response compared with 35 (85.4%) of 41 receiving G-C (p = 0.052). The mean hospital cost of $66,336 for 7 infected patients was significantly higher than that of $8014 in 78 noninfected patients (p < 0.0001). Mean hospital costs of $12,058 and $13,742 for A-C and G-C groups, respectively, were not significantly different (p > 0.05) despite having only a single failure (total cost $162,666) in the A-C group. Similarly, mean pharmacy costs of $1411 and $1604, respectively, were not significantly different (p > 0.05). CONCLUSIONS: Hospital costs for infected patients with penetrating abdominal trauma exceed those of noninfected patients by 5-fold. Despite a lower infection rate in the A-C group, neither hospital nor pharmacy costs were significantly different compared with those in the G-C group.

Recruitment and funding for clinical pharmacy residency and fellowship programs.

A survey was conducted to determine if a shortage exists of graduates interested in residency and fellowship training, and whether program preceptors experience difficulty maintaining funding. Questionnaires were mailed to 195 preceptors listed in the American College of Clinical Pharmacy Directory of Residencies and Fellowships, and responses from 143 (73%) were compiled. Average numbers of applicants interviewed per available position were 3.1, 3.3, and 2.6 for general clinical residency, specialized residency, and fellowship positions, respectively. Approximately 20% of specialty residency and fellowship positions were reported to be unfilled, and 70% of preceptors of these programs expressed the opinion that a shortage of interested graduates exists. Difficulty maintaining funding was most frequently reported by fellowship preceptors (54%), and several sources of funding were required to maintain such programs.

Pharmacokinetics of aztreonam and imipenem in critically ill patients with pneumonia.

STUDY OBJECTIVE: To evaluate the pharmacokinetic profiles of aztreonam and imipenem in critically ill trauma patients with pneumonia. METHODS: Trauma patients in intensive care units who were intubated within 3 days of hospital admission were eligible for the study. Patients with the clinical diagnosis of pneumonia were consecutively randomized to receive either aztreonam plus vancomycin or imipenem-cilastatin. Serial blood samples were taken and sputum was collected to determine aztreonam and imipenem concentrations after 2-3 days and 7-8 days of therapy. Pharmacokinetics of both agents were estimated and compared with estimates from healthy volunteers. RESULTS: Twenty patients were enrolled in the study, 10 patients received imipenem-cilastatin, and 10 received aztreonam plus vancomycin. Steady-state volume of distribution (Vss) for aztreonam at 2-3 days and 7-8 days was significantly greater in patients than in historical controls, whereas the Vss for imipenem was greater at 2-3 days. The beta-half-life for aztreonam at both sampling periods was significantly greater in patients than in controls. No significant changes in pharmacokinetics occurred over time for either antibiotic. Sputum concentrations of aztreonam and imipenem were highly variable when sampled 2 hours after the infusion. CONCLUSION: Larger volumes of distribution were observed for both aztreonam and imipenem in trauma patients than in volunteers, suggesting that standard initial dosages of the antibiotics may result in lower concentrations in these critically ill patients. Both antibiotics penetrated into the sputum of most patients; however, the degree of penetration was highly variable in relation to serum concentrations.

Trimethoprim-sulfamethoxazole pharmacokinetics in trauma patients.

STUDY OBJECTIVES: To characterize the pharmacokinetic profile of trimethoprim-sulfamethoxazole (TMP-SMX) in trauma patients and to compare these parameter estimates with those obtained in nontrauma patients. DESIGN: Open-label, multidose, pharmacokinetic study. SETTING: Trauma intensive care unit of a level 1 trauma center located within a regional medical center. PATIENTS: Fifteen adult trauma patients with serious gram-negative infections. All patients were studied on day 1 of treatment, nine on day 3, three on day 5, and two on day 7. One patient was discontinued from the study because of a possible drug-induced rash. INTERVENTIONS: Study patients received TMP 4 mg/kg and SMX 20 mg/kg intravenously every 12 hours. Serial blood sampling was performed up to 4 times per patient between treatment days 1 and 7. Serum was assayed for TMP-SMX using high-performance liquid chromatography. A one-compartment model was fit to the data using maximum likelihood estimation. MEASUREMENTS AND MAIN RESULTS: Mean (SD) baseline parameter estimates for TMP were volume 2.1 (0.65) L/kg, half-life 9.7 (3.0) hours, and clearance 2.6 (0.80) ml/min/kg. Estimates for SMX were volume 0.51 (0.10) L/kg, half-life 7.8 (2.0) hours, and clearance 0.80 (0.29) ml/min/kg. Both volume (p < 0.01) and clearance (p < 0.001) for SMX were significantly higher and half-life (p < 0.05) significantly shorter than previously reported estimates in nontrauma patients. No significant differences in TMP parameter estimates were found. Neither TMP nor SMX clearance was significantly correlated with estimated creatinine clearance (p > 0.05). CONCLUSION: The results indicate that the pharmacokinetics of SMX in trauma patients differ significantly from nontrauma patients, which may result in lower than expected concentrations using standard dosing guidelines.

The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients.

STUDY OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetic profile of fosphenytoin, a water-soluble phenytoin prodrug, after intramuscular and intravenous administration. DESIGN: Open-label study of intramuscular administration, and double-blind, randomized study of intravenous administration. SETTING: Six and ten hospitals throughout the United States for the intramuscular and intravenous multicenter studies, respectively. PATIENTS: Neurosurgical patients who required anticonvulsant prophylaxis or treatment. INTERVENTIONS: In the intramuscular study, 118 patients received loading doses ranging from 480-1500 mg phenytoin equivalents (PE) and daily maintenance doses ranging from 130-1250 mg PE for 3-14 days. In the intravenous study, 88 patients received fosphenytoin and 28 received phenytoin sodium for 3-14 days. Mean +/- SD loading doses and maintenance doses of intravenous fosphenytoin and phenytoin were 1082 +/- 299 mg PE and 411 +/- 221 mg PE, and 1082 +/- 299 mg and 422 +/- 197 mg, respectively. Trough phenytoin concentrations were measured daily in all patients. MEASUREMENTS AND MAIN RESULTS: Intramuscular fosphenytoin was safe and well tolerated, with no irritation found for 99% of all injection site evaluations. Adverse events associated with the drug occurred in 9% of patients, commonly those typical of the parent drug. For intravenous treatment, the frequency of mild irritation at the infusion site was significantly lower in the fosphenytoin group (6%) than in the phenytoin group (25%, p < 0.05). Reductions in infusion rates were required in 17% and 36% of fosphenytoin and phenytoin recipients, respectively. No significant difference was observed relative to adverse events or seizure frequency between the groups. Trough plasma phenytoin concentrations were approximately 10 micrograms/ml or greater in patients receiving at least 3 days of intramuscular and intravenous fosphenytoin. Trough phenytoin concentrations were similar between patients receiving intravenous phenytoin and fosphenytoin on all study days. CONCLUSION: Fosphenytoin can be administered intramuscularly and intravenously in neurosurgical patients to achieve and maintain therapeutic phenytoin concentrations for up to 14 days. Both routes are safe and well tolerated. Intravenous fosphenytoin is significantly better tolerated than intravenous phenytoin sodium in this patient subset.