New intravenous antibiotics: a focused pharmacotherapy update

Infections due to multidrug-resistant pathogens are increasing throughout the world, in particular due to the emergence of resistant Staphylococcus aureus, vancomycin-resistant enterococcus (VRE) penicillin-resistant Streptococcus pneumonia, multidrug-resistant (MDR) Pseudomonas and Acinetobacter spp, extended-spectrum β-lactamase- (ESBL) producing enteric organisms, etc. These serious pathogens are a major cause of severe hospital and community-acquired infections and are associated with high morbidity and mortality. Several new parenteral antibiotics have been approved in the past several years to help treat these infections, including telavancin, doripenem, tigecycline and daptomycin. This article reviews the pharmacology and limitations of these new antibiotics in treating infections in adult critically ill patients. Despite these advances however, antibiotic research and development continues to be vital in treating infections caused by resistant organisms and addressing current and emerging clinical challenges.1-

Resolution of Clinical Signs of Ventilator-Associated Pneumonia in Trauma Patients

Objectives: The ATS/IDSA Ventilator-Associated Pneumonia (VAP) guidelines suggest that clinical improvement of VAP should be apparent within 3–6 days. This study evaluated resolution of clinical signs of VAP in trauma patients after diagnosis. Methods: Critically injured adults admitted to the trauma intensive care unit (ICU) from June 1, 2006, to December 31, 2007, and subsequently given a diagnosis of VAP were retrospectively assessed. Clinical signs, including derangements of maximum temperature (Tmax), white blood cell (WBC) count, and PaO2/FiO2, were evaluated on days 1–16 after VAP diagnosis. Data are presented as mean ± SD unless otherwise stated. Clinical parameters after VAP were compared using repeated-measures ANOVA with the Tukey test for multiple comparisons. Results: A total of 82 patients were identified. Data for the 34 patients without concurrent infections are presented. Demographic data include: Age 46 ± 17 years; 71% men; 94% blunt trauma; median (IQR) Injury Severity Score 29.5 (24–38); duration of mechanical ventilation 33 ± 27 days; ICU length of stay (LOS) 39 ± 25 days; hospital LOS 53 ± 33 days. Clinical signs following VAP diagnosis: Tmax (°F): Day 1=101.8 ± 1.3, Day 3=101.1 ± 1.1, Day 6=101.1 ± 1.4, Day 16=100.1 ± 3. Compared to Day 1, there was a significant reduction in Tmax at days 10, 11, 12, 13, 14, and 16 (p\u3c0.05 for all). WBC count (cells per microliter): day 1 = 12.9 ± 5, day 3 = 13.7 ± 5, day 6 = 14.4 ± 5, and day 16 = 13.8 ± 6. There was no significant difference in WBC on days 1–16 (p=0.42). PaO2/FiO2: day 1 = 232 ± 108, day 3 = 200 ± 87, day 6 = 218 ± 104, day 16 = 246 ± 126. Differences in PaO2/FiO2 on days 1–16 did not reach statistical significance (p=0.06). Conclusion: Improvement of clinical parameters after a VAP diagnosis is delayed in trauma patients. Alternative methods for determining resolution should be investigated. Published in To be published in Critical Care Medicine’s December 2009 supplement

Resolution of Clinical Signs in Trauma Intensive Care Unit Patients Following Diagnosis of Ventilator-Associated Pneumonia

PURPOSE: The ATS/IDSA Ventilator-Associated Pneumonia (VAP) guidelines suggest that clinical improvement of VAP should be apparent within 3-6 days. Anecdotally, such improvement has not been noted in trauma patients at our institution. The current study was conducted to evaluate resolution of clinical signs of VAP following diagnosis. METHODS: Critically injured adults admitted to the trauma intensive care unit (TICU) from 6/1/06-12/31/07 and subsequently diagnosed with VAP were retrospectively reviewed. Clinical signs, including derangements of maximum temperature (Tmax), white blood cell (WBC) count and Pa02/FiO2, were evaluated on days 1-16 following VAP diagnosis. Data are presented as mean ± SD unless otherwise stated. Clinical parameters following VAP were compared using repeated measures ANOVA with the Tukey test for multiple comparisons. RESULTS: A total of 82 patients were identified. Data for the 34 patients without concurrent infections are presented. Demographic data include: Age 46 ± 17 years; 71% males; 94% blunt trauma; median (IQR) Injury Severity Score 29.5 (24 to 38); duration of mechanical ventilation 33 ± 27 days; ICU length of stay (LOS) 39 ± 25 days; hospital LOS 53 ± 33 days. Clinical signs following VAP diagnosis (Figure): Tmax (°F): Day 1=101.8 ± 1.3, Day 3=101.1 ± 1.1, Day 6=101.1 ± 1.4, Day 16=100.1 ± 3. Compared to Day 1, there was a significant reduction in Tmax at Days 10, 11, 12, 13, 14 and 16 (p \u3c 0.05 for all). WBC count (cells/μL): Day 1=12.9 ± 5, Day 3=13.7 ± 5, Day 6=14.4 ± 5, Day 16=13.8 ± 6. There was no significant difference in WBC count on Days 1-16 (p=0.42). PaO2/FiO2: Day 1=232 ± 108, Day 3=200 ± 87, Day 6=218 ± 104, Day 16=246 ± 126. Differences in PaO2/FiO2 on Days 1-16 did not reach statistical significance (p=0.06). CONCLUSIONS: In trauma patients, improvement of clinical parameters following diagnosis of VAP is delayed beyond the 3-6 day timeframe suggested in the ATS/IDSA guidelines. Alternative methods for determining resolution of VAP in trauma patients should be investigated. METHODS INTRODUCTIO

Hydrochloric Acid Infusion for the Treatment of Metabolic Alkalosis in Surgical Intensive Care Unit Patients

Background: Older reports of use of hydrochloric acid (HCl) infusions for treatment of metabolic alkalosis document variable dosing strategies and risk. Objectives: This study sought to characterize use of HCl infusions in surgical intensive care unit patients for the treatment of metabolic alkalosis. Methods: This retrospective review included patients who received a HCl infusion for \u3e8 hours. The primary end point was to evaluate the utility of common acid-base equations for predicting HCl dose requirements. Secondary end points evaluated adverse effects, efficacy, duration of therapy, and total HCl dose needed to correct metabolic alkalosis. Data on demographics, potential causes of metabolic alkalosis, fluid volume, and duration of diuretics as well as laboratory data were collected. Results: A total of 30 patients were included, and the average HCl infusion rate was 10.5 ± 3.7 mEq/h for an average of 29 ± 14.6 hours. Metabolic alkalosis was primarily diuretic-induced (n = 26). Efficacy was characterized by reduction in the median total serum CO2 from 34 to 27 mM/L (P \u3c 0.001). The change in chloride ion deficit and change in apparent strong ion difference (SIDa) were not correlated with total HCl administered. There were no documented serious adverse effects related to HCl infusions. Conclusion: HCl was effective for treating metabolic alkalosis, and no serious adverse events were seen. In this clinical setting, the baseline chloride ion deficit and SIDa were not useful for prediction of total HCl dose requirement, and serial monitoring of response is recommended

Increased hypoglycemia associated with renal failure during continuous intravenous insulin infusion and specialized nutritional support

Objective: To evaluate glycemic control for critically ill, hyperglycemic trauma patients with renal failure who received concurrent intensive insulin therapy and continuous enteral (EN) or parenteral nutrition (PN). Methods: Adult trauma patients with renal failure, who were given EN or PN concurrently with continuous graduated intravenous regular human insulin (RHI) infusion for at least 3 days were evaluated. Our conventional RHI algorithm was modified for those with renal failure by allowing greater changes in blood glucose concentrations (BG) before the infusion rate was escalated. BG was determined every 1-2 hours while receiving the insulin infusion. BG control was evaluated on the day prior to RHI infusion and for a maximum of 7 days while receiving RHI. Target BG during the RHI infusion was 70 to 149 mg/dL (3.9 to 8.3 mmol/L). Glycemic control and incidence of hypoglycemia for those with renal failure were compared to a historical cohort of critically ill, hyperglycemic trauma patients without renal failure given our conventional RHI algorithm. Results: Twenty-one patients with renal failure who received the modified RHI algorithm were evaluated and compared to forty patients without renal failure given our conventional RHI algorithm. Average BG was significantly greater for those with renal failure (133 + 14 mg/dL or 7.3 + 0.7 mmol/L) compared to those without renal failure (122 + 15 mg/dL or 6.8 + 0.8 mmol/L), respectively (p \u3c 0.01). Patients with renal failure experienced worsened glycemic variability with 16.1 + 3.3 hours/day within the target BG range, 6.9 + 3.2 hours/day above the target BG range, and 1.4 + 1.1 hours below the target BG range compared to 19.6 + 4.7 hours/day (p \u3c 0.001), 3.4 + 3.0 hours/day (p \u3c 0.001), and 0.7 + 0.8 hours/day (p \u3c 0.01) for those without renal failure, respectively. Moderate hypoglycemia (\u3c 60 mg/dL or \u3c 3.3 mmol/L) occurred in 76% of patients with renal failure compared to 35% without renal failure (p \u3c 0.005). Severe hypoglycemia (BG \u3c 40 mg/dL or \u3c 2.2 mmol/L) occurred in 29% of patients with renal failure compared to none of those without renal failure (p \u3c 0.001). Conclusion: Despite receiving a modified RHI infusion, critically ill trauma patients with renal failure are at higher risk for developing hypoglycemia and experience more glycemic variability than patients without renal failure

Resolution of Clinical and Laboratory Abnormalities after Diagnosis of Ventilator-Associated Pneumonia in Trauma Patients

Background: Guidelines advise that patients with ventilator-associated pneumonia (VAP) should respond clinically by Day 3 of antibiotics. White blood cell (WBC) count, maximum temperature (Tmax), and PaO2:FIO2 ratio are all said to respond significantly by Day 6. Resolution of abnormalities has not been evaluated in trauma patients. Methods: Retrospective review of trauma patients with VAP. The WBC count, Tmax, and PaO2:FIO2 were evaluated for 16 days after diagnosis. Patients were grouped into uncomplicated VAP, complicated VAP (those with inadequate empirical therapy [IEAT], VAP relapse/superinfection, or acute respiratory distress syndrome), and concurrent infection +VAP (those also infected at another site). Results: There were 126 patients (uncomplicated VAP= 29, complicated VAP = 69, and concurrent infection + VAP = 28). The mean Tmax in patients with uncomplicated VAP decreased significantly from diagnosis to Day 4 (Day 1: 39 – 0.5°C vs. Day 4: 38.6 – 0.7°C; p = 0.028) but never normalized. Their WBC counts and PaO2:FIO2 did not change significantly over the 16-day follow-up and never normalized.When comparing the three groups, the probability of resolving all three abnormalities was not different (p = 0.5). Conclusions: Clinical and laboratory abnormalities in critically injured patients with VAP do not resolve as quickly as suggested in the guidelines. Future studies should evaluate new methods to determine the response to antibiotic therapy in critically injured patients with VAP

Candidate gene analysis of femoral neck trabecular and cortical volumetric bone mineral density in older men.

In contrast to conventional dual-energy X-ray absorptiometry, quantitative computed tomography separately measures trabecular and cortical volumetric bone mineral density (vBMD). Little is known about the genetic variants associated with trabecular and cortical vBMD in humans, although both may be important for determining bone strength and osteoporotic risk. In the current analysis, we tested the hypothesis that there are genetic variants associated with trabecular and cortical vBMD at the femoral neck by genotyping 4608 tagging and potentially functional single-nucleotide polymorphisms (SNPs) in 383 bone metabolism candidate genes in 822 Caucasian men aged 65 years or older from the Osteoporotic Fractures in Men Study (MrOS). Promising SNP associations then were tested for replication in an additional 1155 men from the same study. We identified SNPs in five genes (IFNAR2, NFATC1, SMAD1, HOXA, and KLF10) that were robustly associated with cortical vBMD and SNPs in nine genes (APC, ATF2, BMP3, BMP7, FGF18, FLT1, TGFB3, THRB, and RUNX1) that were robustly associated with trabecular vBMD. There was no overlap between genes associated with cortical vBMD and trabecular vBMD. These findings identify novel genetic variants for cortical and trabecular vBMD and raise the possibility that some genetic loci may be unique for each bone compartment