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.

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.

Intermittent and continuous ceftazidime infusion for critically ill trauma patients.

BACKGROUND: The adequacy of intermittent and continuous infusion ceftazidime for the treatment of nosocomial pneumonia in critically ill trauma patients was assessed by analyzing ceftazidime pharmacokinetics in relation to the minimum inhibitory concentration (MIC) and treatment outcome. METHODS: Serial blood samples were obtained during ceftazidime therapy in 31 trauma patients. Ceftazidime pharmacokinetics were compared with that of previously studied healthy volunteers. Ceftazidime pharmacokinetics were analyzed according to the time above the MIC and treatment outcome. RESULTS: Critically ill trauma patients had a significantly increased volume of distribution and clearance (0.32 +/- 0.14 L/kg and 2.35 +/- 0.89 mL. min(-1). kg(-1), respectively) compared with healthy volunteers (0.21 +/- 0.03 and 1.58 +/- 0.23 mL. min(-1). kg(-1)). The time above the MIC was >/=92% of the dosing interval for all patients and treatment outcomes were similar between the two treatment groups. CONCLUSIONS: Ceftazidime pharmacokinetics are significantly altered in critically ill trauma patients. Both intermittent and continuous ceftazidime regimens were equally effective for the treatment of nosocomial pneumonia caused by less virulent bacteria.

Role of aztreonam in the treatment of nosocomial pneumonia in the critically ill surgical patient.

In 1995 the American Thoracic Society issued an official consensus statement on the treatment of hospital-acquired pneumonia (HAP). Classes of antimicrobials included in the list of antimicrobials deemed to be suitable for the empiric treatment of severe HAP were the aminoglycosides, quinolones, antipseudomonal penicillins, carbapenems, and beta-lactam/beta-lactamase inhibitor combinations. Aztreonam, a monobactam, was also listed and is unique among these agents based on its spectrum of activity being limited to the gram-negative bacillary bacteria combined with an excellent safety profile. This review focuses on the role of aztreonam in the treatment of nosocomial pneumonia in the critically ill patient.A review of the literature was performed using PubMed and secondary literature sources as to the clinical efficacy of aztreonam in the treatment of lower respiratory tract infections as well as its pharmacokinetic and safety profiles. An analysis of aztreonam's potential pharmacoeconomic advantages compared with other agents was also performed. Numerous studies have documented that aztreonam has effectiveness that is equal or superior to that of other suitable antibiotics in the treatment of nosocomial pneumonia. Its excellent safety profile makes it a particularly attractive agent compared with the aminoglycosides. Considering the potential costs of bacterial resistance from the use of broader-spectrum alternatives, a case can be made that aztreonam is a pharmacoeconomically sound choice as well.

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.

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.

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.

Fluconazole pharmacokinetics in burn patients.

The pharmacokinetics of fluconazole in nine adult patients with severe (30 to 95% total body surface area) burns were studied. There was no significant difference in half-life (t1/2), clearance (CL), or volume of distribution (V) over time in five patients on days 3 and 8 of the study (P > 0.05). Combined parameter estimates (means +/- standard deviations) for all nine patients for the two study periods were as follows: t1/2, 24.4 +/- 5.8 h; CL, 0.36 +/- 0.09 ml/min/kg; and V, 0.72 +/- 0.12 liters/kg. These estimates of t1/2 and CL in burn patients were approximately 13% shorter and 30% more rapid, respectively, than the most extreme estimates reported for other populations.

Incidence and risk factors of thrombocytopenia in critically ill trauma patients.

OBJECTIVE: To determine the incidence of thrombocytopenia (< 100 platelets x 10(3)/mm3) and potential risk factors, including medications, associated with the development of thrombocytopenia in critically ill trauma patients. DESIGN: Prospective, observational study. SETTING: A 20-bed trauma intensive care unit (ICU) at a university hospital. PATIENTS: Sixty-three critically ill trauma patients without baseline thrombocytopenia admitted to the trauma ICU for at least 48 hours. INTERVENTIONS: Patients were followed for up to 14 days. Platelet counts were determined daily. The following data were collected and analyzed as potential risk factors for the development of thrombocytopenia: medications, age, sex, race, trauma score, mode and type of injury, alcohol history, units of packed red blood cells (PRBC) and platelets transfused, surgical procedures, duration of ICU stay, and the development of systemic inflammatory response syndrome or disseminated intravascular coagulation. RESULTS: Thrombocytopenia occurred in 26 (41%) of the patients. Among risk factors studied, nonhead injury, age, trauma score, duration of ICU stay, and the number of PRBC transfusions were significantly associated with the development of thrombocytopenia (p < 0.05). However, nonhead injury, age, and trauma score were useful variables in predicting the development of thrombocytopenia by using multivariate analysis. Medications were not associated with the development of thrombocytopenia. CONCLUSIONS: The type of injury sustained, the quantity of platelet-deficient, transfusions, and age are the greatest risk factors associated with the development of thrombocytopenia in critically ill trauma patients. Drug-induced thrombocytopenia appears to play a minor role in the development of thrombocytopenia; therefore, medications should not be automatically discontinued or substituted when thrombocytopenia occurs.

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.

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.

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.

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.

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.

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.

Current patterns of prescribing and administering morphine in trauma patients.

We attempted to characterize the current prescribing practices and administration patterns for intravenous intermittent morphine in trauma patients in a multicenter, open prospective, observational study. The subjects were 141 patients admitted to the surgical intensive care units (ICU) of five United States trauma centers within 12 hours of injury who received intermittent intravenous morphine for pain relief. The study was conducted from April 15, 1992, to February 15, 1993. Data obtained during the first 32 hours of the ICU stay included morphine regimen, doses administered, and time between doses. One hundred sixty-one orders were prescribed by surgeons. The most frequently ordered dose was 2-4 mg and the most frequently ordered interval was every hour as necessary. There was no relationship between the severity of injury and the minimum dose ordered. During the 492 nursing shifts studied, 1257 doses were administered. Of these, 44% were at or below the minimum amount prescribed by the surgeons. Thirty-three percent of the patients received a dose at an interval of more than 3 hours. We concluded that small amounts of narcotic analgesics are given to severely injured patients, and amount ordered is not affected by the severity of injury.

Advances in pharmacotherapy: treatment of hypertensive crisis.

A hypertensive crisis can be caused by many factors. Frequently, the mechanism involved is complex and highly variable among patients. Without drug therapy, this condition is associated with very high mortality and morbidity. There are a number of oral and intravenous hypotensive agents available, which can effectively control blood pressure in a hypertensive crisis. The relative advantages and disadvantages of each treatment option is discussed.