Seth R. Bauer

Association Between Colistin Dose and Microbiologic Outcomes in Patients With Multidrug-Resistant Gram-Negative Bacteremia

BACKGROUND Colistin is increasingly used for the treatment of multidrug-resistant gram-negative infections. However, colistin dosing varies greatly and the optimal regimen is unknown. The purpose of this study was to determine if colistin dosing correlates with patient outcomes. METHODS This retrospective study included patients with gram-negative bacteremia treated with intravenous colistin for at least 72 hours. The primary objective was to determine if colistin dose (mg of colistin base activity/kg/day) independently predicts day-7 microbiological success. Secondary objectives included evaluation for an association between colistin dose and 7-day mortality, 28-day mortality, and the development of acute kidney insufficiency (AKI). RESULTS Seventy-six patients were included in the analysis, with 52 patients (68%) achieving 7-day microbiological success. The median colistin dose was significantly higher in patients who achieved microbiological success (2.9 vs 1.5 mg/kg/day; P = .011). After adjusting for baseline severity of illness and concomitant tigecyline use, higher colistin dose independently correlated with microbiological success (adjusted odds ratio per 1 mg/kg/day = 1.74; 95% confidence interval, 1.11-2.71; P = .015). The median colistin dose was also significantly higher among survivors at day 7 (2.7 vs 1.5 mg/kg/day; P = .007). However, no difference was observed in colistin dose when comparing survivors and nonsurvivors at day 28. A significantly higher colistin dose was given to patients who developed AKI during therapy (3.8 vs 1.6 mg/kg/day; P < .001). CONCLUSIONS Higher colistin dose independently predicted microbiological success, which may partially explain the similar association with 7-day mortality. However, higher colistin doses may also precipitate worsening renal function.

Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

BACKGROUND AND OBJECTIVES Current recommendations for piperacillin-tazobactam dosing in patients receiving continuous renal replacement therapy originate from studies with relatively few patients and lower continuous renal replacement therapy doses than commonly used today. This study measured the pharmacokinetic and pharmacodynamic characteristics of piperacillin-tazobactam in patients treated with continuous renal replacement therapy using contemporary equipment and prescriptions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A multicenter prospective observational study in the intensive care units of two academic medical centers was performed, enrolling patients with AKI or ESRD receiving piperacillin-tazobactam while being treated with continuous renal replacement therapy. Pregnant women, children, and patients with end stage liver disease were excluded from enrollment. Plasma and continuous renal replacement therapy effluent samples were analyzed for piperacillin and tazobactam levels using HPLC. Pharmacokinetic and pharmacodynamic parameters were calculated using standard equations. Multivariate analyses were used to examine the association of patient and continuous renal replacement therapy characteristics with piperacillin pharmacokinetic parameters. RESULTS Forty-two of fifty-five subjects enrolled had complete sampling. Volume of distribution (median=0.38 L/kg, intraquartile range=0.20 L/kg) and elimination rate constants (median=0.104 h(-1), intraquartile range=0.052 h(-1)) were highly variable, and clinical parameters could explain only a small fraction of the large variability in pharmacokinetic parameters. Probability of target attainment for piperacillin was 83% for total drug but only 77% when the unbound fraction was considered. CONCLUSIONS There is significant patient to patient variability in pharmacokinetic/pharmacodynamic parameters in patients receiving continuous renal replacement therapy. Many patients did not achieve pharmacodynamic targets, suggesting that therapeutic drug monitoring might optimize therapy.

Effect of corticosteroids on arginine vasopressin–containing vasopressor therapy for septic shock: a case control study

PURPOSE Studies showing corticosteroids decrease time to shock reversal in septic shock did not include arginine vasopressin, which also may reduce the duration of catecholamine therapy. Thus, the effect of corticosteroids on vasopressin-containing vasopressor regimens is unknown. We designed this study to evaluate the effect of corticosteroids on time to vasopressin-containing vasopressor withdrawal and the proportion of patients alive without vasopressors at day 7. METHODS This retrospective, case-control study included patients admitted to the intensive care units of an academic medical center who received vasopressin-containing vasopressor regimens for septic shock with or without concomitant corticosteroids. Twenty-one corticosteroid-treated patients were matched to those without corticosteroids. RESULTS Both groups had similar Acute Physiology And Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) II, and Sequential Organ Failure Assessment (SOFA) scores. There was no significant difference in median time to vasopressor withdrawal (65 hours vs 20 hours, P = .09) whether corticosteroids were given or withheld. Patients who received corticosteroids, however, were significantly more likely alive without vasopressors at day 7 than patients who received a vasopressin-containing vasopressor regimen alone (80.9% vs 47.6%, P = .02). CONCLUSIONS Although corticosteroids did not improve the time to withdrawal of vasopressin-containing vasopressor therapy they significantly increased the proportion of patients alive without vasopressors at day 7.

Therapeutic Drug Monitoring of Piperacillin-Tazobactam Using Spent Dialysate Effluent in Patients Receiving Continuous Venovenous Hemodialysis

ABSTRACT Sepsis and multisystem organ failure are common diagnoses affecting nearly three-quarters of a million Americans annually. Infection is the leading cause of death in acute kidney injury, and the majority of critically ill patients who receive continuous dialysis also receive antibiotics. Dialysis equipment and prescriptions have gradually changed over time, raising concern that current drug dosing recommendations in the literature may result in underdosing of antibiotics. Our research group directed its attention toward antibiotic dosing strategies in patients with acute renal failure (ARF), and we sought data confirming that patients receiving continuous dialysis and antibiotics actually were achieving therapeutic plasma drug levels during treatment. In the course of those investigations, we explored “fast-track” strategies to estimate plasma drug concentrations. As most antimicrobial antibiotics are small molecules and should pass freely through modern high-flux hemodialyzer filters, we hypothesized that continuous renal replacement therapy (CRRT) effluent could be used as the medium for drug concentration measurement by reverse-phase high-pressure liquid chromatography (HPLC). Here we present the first data demonstrating this approach for piperacillin-tazobactam. Paired blood and dialysate trough-peak-trough samples were drawn from 19 patients receiving piperacillin-tazobactam and continuous venovenous hemodialysis (CVVHD). Total, free, and dialysate drug concentrations were measured by HPLC. Dialysate drug levels predicted plasma free drug levels well (r 2 = 0.91 and 0.92 for piperacillin and tazobactam, respectively) in all patients. These data suggest a strategy for therapeutic drug monitoring that minimizes blood loss from phlebotomy and simplifies analytic procedures.

Effect of Body Mass Index on Bleeding Frequency and Activated Partial Thromboplastin Time in Weight-Based Dosing of Unfractionated Heparin: A Retrospective Cohort Study

OBJECTIVE To assess bleeding and activated partial thromboplastin time (APTT) in relation to body mass index (BMI) in patients prescribed weight-based dosing of intravenous unfractionated heparin (UFH) for cardiac indications without a maximum (dose-capped) initial bolus or capped initial infusion rate. PATIENTS AND METHODS Consecutive patients admitted to an academic medical center from February 1, 2002, through November 31, 2003, who were treated with a UFH nomogram consisting of a 60-U/kg intravenous bolus plus an initial continuous intravenous infusion of 12 U/kg hourly and titrated to a goal APTT range corresponding to thromboplastin-adjusted target heparin levels of 0.3 to 0.7 U/mL by anti-Xa assay were evaluated for this retrospective cohort study. Patients were excluded if they concomitantly received a fibrinolytic, glycoprotein IIb/IIIa inhibitor, or any other antithrombotic agent (except warfarin). Study patients were divided into quartiles by BMI. RESULTS Of the 1054 patients included in the study, 807 (76.6%) had an initial bolus dose higher than 4000 U, and 477 (45.3%) had an initial infusion rate higher than 1000 U/h. Despite a significant difference among BMI quartiles in proportion of supratherapeutic first APTT values (P<.001), no statistically significant difference was found in bleeding frequency (P=.26) or frequency of first APTT within the goal range (P=.27). Logistic regression analyses revealed that BMI was not a significant predictor of bleeding or first APTT within the goal range. CONCLUSION We did not find any difference in the proportion of first APTT values in the goal range or an increased risk of bleeding in obese patients treated with UFH without a capped initial dose. Our data demonstrate the safe use of weight-based UFH without a capped initial bolus dose or capped initial infusion rate in patients with medical cardiac conditions.

Comparison of treatment outcomes with vancomycin alone versus combination therapy in severe Clostridium difficile infection

BACKGROUND The recommended treatment for severe Clostridium difficile infection (CDI) is oral vancomycin alone. Combination therapy with metronidazole is only recommended in cases complicated by shock, ileus, or toxic megacolon. However, patients with severe infection are often treated with combination therapy despite a lack of data supporting this practice. AIM To evaluate differences in outcomes for patients with severe CDI treated with oral vancomycin alone versus combination therapy. METHODS Medical records of 78 patients with severe CDI receiving either oral vancomycin alone or combination therapy for ≥ 72h were retrospectively reviewed. The primary outcome was time to clinical cure of CDI, defined as the first day of resolution of diarrhoea for ≥ 48h without development of a complication. Other endpoints included cure rates, complication rates, and recurrence rates. FINDINGS There was no difference in the incidence of clinical cure between monotherapy and combination therapy (57.1% vs 65.1%, P = 0.49). Median time to clinical cure was 7.0 days for the monotherapy group and 8.0 days for combination therapy (P = 0.19). After adjustment for potential confounders, the hazard ratio of the time to clinical cure for combination therapy compared with monotherapy was 0.58 (P = 0.10). There was no difference in recurrence rate or rates of individual complications between groups; however, there was a significantly higher composite complication rate in the combination therapy group. CONCLUSION These data suggest that there is no difference in treatment outcomes between monotherapy and combination therapy for severe CDI.

Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli

ABSTRACT The increasing prevalence of multidrug-resistant (MDR) nosocomial infections accounts for increased morbidity and mortality of such infections. Infections with MDR Gram-negative isolates are frequently treated with colistin. Based on recent pharmacokinetic studies, current colistin dosing regimens may result in a prolonged time to therapeutic concentrations, leading to suboptimal and delayed effective treatment. In addition, studies have demonstrated an association between an increased colistin dose and improved clinical outcomes. However, the specific dose at which these outcomes are observed is unknown and warrants further investigation. This retrospective study utilized classification and regression tree (CART) analysis to determine the dose of colistin most predictive of global cure at day 7 of therapy. Patients were assigned to high- and low-dose cohorts based on the CART-established breakpoint. The secondary outcomes included microbiologic outcomes, clinical cure, global cure, lengths of intensive care unit (ICU) and hospital stays, and 7- and 28-day mortalities. Additionally, safety outcomes focused on the incidence of nephrotoxicity associated with high-dose colistin therapy. The CART-established breakpoint for high-dose colistin was determined to be >4.4 mg/kg of body weight/day, based on ideal body weight. This study evaluated 127 patients; 45 (35%) received high-dose colistin, and 82 (65%) received low-dose colistin. High-dose colistin was associated with day 7 global cure (40% versus 19.5%; P = 0.013) in bivariate and multivariate analyses (odds ratio [OR] = 3.40; 95% confidence interval [CI], 1.37 to 8.45; P = 0.008). High-dose colistin therapy was also associated with day 7 clinical cure, microbiologic success, and mortality but not with the development of acute kidney injury. We concluded that high-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 global cure.

Lactic acidosis: Clinical implications and management strategies

In hospitalized patients, elevated serum lactate levels are both a marker of risk and a target of therapy. The authors describe the mechanisms underlying lactate elevations, note the risks associated with lactic acidosis, and outline a strategy for its treatment. In hospitalized patients, elevated lactate is both a marker of risk and a target of therapy.

Impact of Combination Antimicrobial Therapy on Mortality Risk for Critically Ill Patients with Carbapenem-Resistant Bacteremia

ABSTRACT There are limited treatment options for carbapenem-resistant Gram-negative infections. Currently, there are suggestions in the literature that combination therapy should be used, which frequently includes antibiotics to which the causative pathogen demonstrates in vitro resistance. This case-control study evaluated risk factors associated with all-cause mortality rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. Adult patients who were admitted to an intensive care unit with sepsis and a blood culture positive for Gram-negative bacteria resistant to a carbapenem were included. Patients with polymicrobial, recurrent, or breakthrough infections were excluded. Included patients were classified as survivors (controls) or nonsurvivors (cases) at 30 days after the positive blood culture. Of 302 patients screened, 168 patients were included, of whom 90 patients died (53.6% [cases]) and 78 survived (46.4% [controls]) at 30 days. More survivors received appropriate antibiotics (antibiotics with in vitro activity) than did nonsurvivors (93.6% versus 53.3%; P < 0.01). Combination therapy, defined as multiple appropriate agents given for 48 h or more, was more common among survivors than nonsurvivors (32.1% versus 7.8%; P < 0.01); however, there was no difference in multiple-agent use when in vitro activity was not considered (including combinations with carbapenems) (87.2% versus 80%; P = 0.21). After adjustment for baseline factors with multivariable logistic regression, combination therapy was independently associated with decreased risk of death (odds ratio, 0.19 [95% confidence interval, 0.06 to 0.56]; P < 0.01). These data suggest that combination therapy with multiple agents with in vitro activity is associated with improved survival rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. However, that association is lost if in vitro activity is not considered.

Effect of vancomycin dose on treatment outcomes in severe Clostridium difficile infection

Current guidelines recommend vancomycin 125 mg four times daily for the treatment of severe Clostridium difficile infection (CDI). However, the optimal dose of vancomycin has not been elucidated. This study was conducted to evaluate outcome differences in patients with severe CDI treated with either low-dose (≤500 mg daily) or high-dose (>500 mg daily) oral vancomycin. The medical records of 78 patients with severe CDI were evaluated retrospectively. The primary outcome was time to clinical cure of CDI, defined as the first day of resolution of diarrhoea for ≥48 h without development of a complication. Other endpoints included cure rates, complication rates and recurrence rates. Overall, 48 patients (61.5%) achieved clinical cure at Day 10 after treatment initiation. The cure rates in the high-dose and low-dose vancomycin groups were 60% and 64%, respectively (P = 0.76). Using a multivariate Cox proportional hazards model adjusting for baseline discrepancies, vancomycin dose was not independently associated with clinical cure. No difference in time to cure, complication rates or mortality was observed between the groups. There was a trend towards lower rates of recurrence associated with higher doses of oral vancomycin (12% vs. 1.9%; P = 0.09). In conclusion, these data suggest that there is no difference in treatment outcomes between high-dose and low-dose vancomycin for the treatment of severe CDI. The potential difference in recurrence rates between the groups warrants further investigation.