Bradley A. Boucher

Comparison of ampicillin-sulbactam and imipenem-cilastatin for the treatment of Acinetobacter ventilator-associated pneumonia

Acinetobacter organisms, which are a common cause of ventilator-associated pneumonia (VAP) in some health care centers, are becoming more resistant to such first-line agents as imipenem-cilastatin (Imi-Cil). Sulbactam has good in vitro activity against Acinetobacter organisms; thus, ampicillin-sulbactam (Amp-Sulb) may be a viable treatment alternative. The outcomes for critically ill trauma patients with Acinetobacter VAP treated with either Amp-Sulb or Imi-Cil were compared retrospectively. A total of 77 episodes in 75 patients were studied. Fourteen patients were treated with Amp-Sulb, and 63 patients were treated with Imi-Cil. Treatment efficacy was similar in the Amp-Sulb and Imi-Cil groups (93% vs. 83%, respectively; P>.05). No statistically significant differences between groups were noted with regard to associated mortality, duration of mechanical ventilation, or length of stay in the intensive care unit or hospital. However, adjunctive aminoglycoside therapy was used more often in the Amp-Sulb group. Patients generally received Amp-Sulb because of imipenem resistance. Amp-Sulb was effective in treating a small number of patients with Acinetobacter VAP; however, more data are needed.

Risk Factors for Late-Onset Nosocomial Pneumonia Caused by Stenotrophomonas maltophilia in Critically Ill Trauma Patients

Patients with nosocomial pneumonia caused by Stenotrophomonas maltophilia often receive inadequate empiric antibiotic therapy, potentially increasing mortality. Knowledge of the risk factors associated with S. maltophilia pneumonia may better guide the selection of empiric antibiotic therapy. Potential risk factors for S. maltophilia pneumonia were retrospectively analyzed for critically ill trauma patients with late-onset gram-negative pneumonia. The effects of S. maltophilia infection and inadequate empiric antibiotic therapy on patient outcomes were also assessed. By multivariate analysis, S. maltophilia pneumonia was found to be associated with cefepime exposure and tracheostomy in patients with a single pneumonia episode and with higher Injury Severity Score and pulmonary contusion in patients with multiple pneumonia episodes. S. maltophilia pneumonia was associated with increased patient morbidity; only inadequate empiric antibiotic therapy was associated with a higher mortality rate. In critically ill trauma patients with late-onset ventilator-associated pneumonia and these risk factors, empiric antibiotic therapy should include agents active against S. maltophilia.

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.

Tetracyclines for treating multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia

ObjectiveTo report the use of tetracyclines for the treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP).DesignObservational case series.SettingThe Presley Regional Trauma Center located within the Regional Medical Center, Memphis, Tennessee, USA.Patients and participantsSeven critically ill trauma patients with VAP caused by A. baumannii isolates that were resistant to all antibiotics tested except for doxycycline or minocycline.InterventionsPatients were treated with IV doxycycline or minocycline for an average of 13.5 (range 9–20) days.Measurements and resultsDoxycycline or minocycline was successful in six of seven patients.ConclusionsDoxycycline or minocycline may be effective for treating multidrug-resistant A. baumannii VAP.

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

Objective To determine the incidence of thrombocytopenia (<100 platelets × 103/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 significanüy 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 from multiple episodes of inadequate empiric antibiotic therapy for ventilator-associated pneumonia on morbidity and mortality among critically ill trauma patients.

BACKGROUND Empiric antibiotic therapy is routinely initiated for patients with presumed ventilator-associated pneumonia (VAP). The impact of inadequate empiric antibiotic therapy (IEAT) may vary among critically ill populations. The purpose of this retrospective study was to determine the effect of IEAT on the outcome for adult trauma patients with VAP. METHODS This study enrolled 82 patients with multiple VAP episodes (200 VAP episodes; mean, 2.4 +/- 0.65 per patient; range, 2-5 episodes). An episode of IEAT was a VAP episode with empiric therapy having no in vitro activity against causative bacteria. Overall, there were 78 (39%) IEAT episodes involving 54 patients. Most often, IEAT was attributable to the presence of Acinetobacter spp, Stenotrophomonas maltophilia, or Alcaligenes xylosoxidans. All the patients received appropriate definitive therapy according to the final culture. The patients were classified by number of IEAT episodes: 0 (n = 28), 1 (n = 34), and more than 1 (n = 20). RESULTS Demographics and injury severity were similar among the groups. The mortality rate was 3.6% for no episodes, 8.8% for one episode, and 45% for more than one episode (p < 0.001). On the basis of multiple logistic regression, experiencing multiple IEAT episodes was independently associated with the risk of death (odds ratio, 4.28; 95% confidence interval, 1.44-12.71). Additionally, experiencing multiple IEAT episodes was associated with prolonged intensive care unit stay (p = 0.007) and prolonged mechanical ventilation (p = 0.005). CONCLUSIONS Critically ill trauma patients experiencing multiple episodes of IEAT for VAP have increased morbidity and mortality. These findings reinforce the importance of developing and refining a unit-specific pathway for the empiric management of VAP.

Aerosolized ceftazidime for prevention of ventilator-associated pneumonia and drug effects on the proinflammatory response in critically ill trauma patients

Study Objectives. To evaluate the safety and efficacy of aerosolized ceftazidime for prevention of ventilator‐associated pneumonia (VAP) and to evaluate the effects of the drug on the proinflammatory response.

The appropriate diagnostic threshold for ventilator-associated pneumonia using quatititative cultures

BACKGROUND The use of quantitative cultures of the bronchoalveolar lavage (BAL) effluent to distinguish between posttraumatic inflammatory response and ventilator-associated pneumonia (VAP) is becoming more common. However, the diagnostic threshold of either 10 or 10 colonies/mL remains debatable. Because mortality from VAP is related to treatment delay, some have chosen a lower diagnostic threshold (>10 colonies/mL). This may result in unnecessary antibiotic use with its sequelae: increased resistant organisms, antibiotic-related complications, and increased costs. The purpose of this study is to determine the optimal diagnostic threshold for VAP diagnosis using quantitative cultures of the BAL effluent. METHODS Data on patients with fiberoptic bronchoscopy with BAL are maintained in a prospectively collected database at our Level I trauma center. This database was reviewed for timing and frequency of BAL and the colony counts of each organism identified. Indication for bronchoscopy was clinical evidence of VAP. VAP was defined as >10 colonies/mL in the BAL effluent. A false-negative BAL was defined as any patient who had <10 colonies/mL and developed VAP with the same organism up to 7 days after the previous culture. RESULTS Over a 46-month period, 526 patients underwent 1,372 fiberoptic bronchoscopy procedures with BAL. Of these, 72% were male patients, 91% followed blunt injury, and mean age and Injury Severity Score were 43 years and 30, respectively. Overall mortality was 14%. There were 1,898 organisms identified (42% were gram-positive and 58% were gram-negative). VAP was diagnosed in 38% of BAL. Overall, there were 43 episodes in 38 patients defined as false-negative (3%). The false-negative rate was 9% in patients with 10 organisms. The most common false-negative organisms were Pseudomonas and Acinetobacter species. CONCLUSION The VAP diagnostic threshold for quantitative BAL in trauma patients should be >10 colonies/mL. One may consider a threshold of >10 colonies/mL in severely injured patients with Pseudomonas or Acinetobacter species.

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.

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 α1-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 increases 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.