Resistance in the intensive care unit: whose problem is it and how can intensivists help?
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Anti-Bacterial Agents↗
Biomedical subjects
Jeffrey Lipman
Publications and source records attributed to Jeffrey Lipman.
Cefepime versus ceftazidime: considerations for empirical use in critically ill patients.
Sepsis and nosocomial infections continue to be a significant problem in intensive care, contributing heavily to mortality and prolonged hospital stay. Early and appropriate antibiotic therapy is critical for optimising outcomes. However, the emergence of highly resistant bacteria, coupled with reduced development of novel antibiotics, means that there is a real threat of development of untreatable nosocomial infections. Cefepime and ceftazidime are broad-spectrum cephalosporins that are widely used to treat Gram-negative nosocomial infections in critically ill patients. Available data suggest that cefepime may have advantages over ceftazidime owing to a broader spectrum of activity and reduced potential for development of bacterial resistance. However, whether either of these agents is superior can only be determined by a head-to-head study evaluating clinical and bacteriological outcomes. Such a study to determine whether apparent differences translate into clinically relevant differences in outcome is indicated.
Anti-Bacterial Agents↗
Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study.
OBJECTIVES: To compare the clinical and bacteriological outcome of critically ill patients with sepsis treated by ceftriaxone administered as a once-a-day intermittent bolus dose or by 24 h continuous infusion. PATIENTS AND METHODS: We conducted an open-label, randomized controlled pilot study in 57 patients clinically diagnosed with sepsis (suspected/proven infection and systemic inflammatory response syndrome) in a tertiary level intensive care unit. Patients were randomized to receive 2 g of ceftriaxone administered by once-daily intermittent bolus dosing or by 24 h continuous infusion. Clinical and bacteriological outcomes were assessed by blinded clinicians. RESULTS: Fifty-seven patients were enrolled in the study, 50 of whom fulfilled the a priori definition of treatment for 4 or more days. The infusion (n = 29) and bolus groups (n = 28) were similar in terms of demographics, although the median age of those receiving the infusion was younger. Intention-to-treat analysis found no statistically significant differences in the primary outcomes for clinical response (P = 0.17), clinical cure [infusion n = 13/29 versus bolus n = 5/28; adjusted odds ratio (AOR) = 3.74; 95% confidence interval (95% CI) = 1.11-12.57; P = 0.06], bacteriological response (P = 0.41) and bacteriological cure (infusion n = 18/29 versus bolus 14/28; AOR = 1.64; 95% CI = 0.57-4.70; P = 0.52). However, logistic regression in patients that complied with the a priori definitions who received ceftriaxone by continuous infusion (AOR = 22.8; 95% CI = 2.24-232.3; P = 0.008) or patients with a low Acute Physiology and Chronic Health Evaluation (APACHE) II score (AOR = 0.70; 95% CI = 0.54-0.91; P = 0.008) were associated with an improved clinical outcome when age and Sepsis Organ Failure Assessment (SOFA) score at time of study entry were controlled for. CONCLUSIONS: This pilot study suggests clinical and bacteriological advantages of continuous infusion of ceftriaxone over bolus administration in critically ill patients in patients requiring 4 or more days of treatment. This sets the scene for a large multicentre double-blind randomized controlled trial to confirm these findings.
APACHE↗
Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units.
OBJECTIVES: (i) To develop a population pharmacokinetics (PK) model for cefepime in patients in intensive care units (ICUs). (ii) To assess the pharmacokinetic-pharmacodynamic profile of various cefepime dosing regimens and to assess their expected probability of target attainment (=PTA expectation value) against common ICU pathogens such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. METHODS: Thirteen ICU patients received cefepime 2 g 12 hourly intravenous (3 min). Twelve blood samples were taken on two occasions: (i) immediately after initial dose; and (ii) between days 3 and 6 after starting therapy. Population PK models were developed using NONMEM. Based on the final covariate model, Monte Carlo simulations were undertaken (n=1000) to simulate free-drug concentrations of cefepime for two administration methods: (i) intermittent bolus administration (IBA); and (ii) continuous infusion (CI). Concentration-time profiles were evaluated by the probability of achieving free-drug concentration above the MIC for >65% of the dosing interval. Finally, using local MIC distributions of E. coli, K. pneumoniae, P. aeruginosa and A. baumannii the PTA expectation values for each dosing administration method were evaluated. RESULTS: A three-compartment model with zero-order input best described the concentration-time data. The PTA expectation values for E. coli and K. pneumoniae were >90% in all CI doses but only when administered as 1 g every 6 h and higher daily doses for IBA. For the current treatment protocol, 2 g every 12 h, P. aeruginosa and A. baumannii achieved target concentrations of only 54% and 28%, respectively. For P. aeruginosa, a CI of at least 4 g/day was required to achieve a PTA expectation value>90% while for A. baumannii a 6 g/day CI only achieved a PTA expectation value of 75%. CONCLUSIONS: When given as IBA or CI for E. coli and K. pneumoniae, cefepime should be successful in achieving the bactericidal target. For P. aeruginosa higher doses of cefepime (>4 g/day) are required to achieve the required PTA expectation value. Cefepime fails to achieve the bactericidal target even when administered at high doses, e.g. 6 g/day, for A. baumannii.
Acinetobacter Infections↗
Positioning practices for ventilated intensive care patients: current practice, indications and contraindications.
To investigate the process of providing patient positioning in intensive care units (ICUs), a self-reported survey was distributed to a senior physiotherapist and a nurse in each of the 38 Level 3 Australian ICUs. The survey explored the rationales, aims, type, frequency and duration of directed patient positioning used, and perceived risks that may impede the implementation of an effective positioning regime. The response rate was 93%. Fifty nine respondents (83%) agreed that there is an accepted standard of care for the duration of a position change with ventilated patients. Of these respondents, 51 (86%) agreed that the standard is to turn patients every 2 hours, but this was only achievable "more than 50% of the time" in 47% (n=34) of ICUs. Educational and environmental issues were found to impact on positioning practices. Semi-recumbent and full side-lie positions were recommended in the management of a range of patient conditions. However, full side-lie was less commonly used than supine positioning. The prone and head down tilt positions were the least frequently utilised. Levels of agreement for precautions and contraindications to positioning patients into full side-lie and sitting were high. We conclude that, in Australia, experienced ICU physiotherapy and nursing staff are aware of evidence-based positioning practices and agree on indications and potential risk factors associated with positioning. However, educational and environmental resources are needed to improve the frequency and type of positioning used. Results from this survey can now be incorporated into educational tools to facilitate the safe use of positioning.
Attitude of Health Personnel↗
Making the wrong choice: Consequences for patients with infections due to methicillin-resistant Staphylococcus aureus.
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Anti-Bacterial Agents↗
Antibacterial dosing in intensive care: pharmacokinetics, degree of disease and pharmacodynamics of sepsis.
Treatment of sepsis remains a significant challenge with persisting high mortality and morbidity. Early and appropriate antibacterial therapy remains an important intervention for such patients. To optimise antibacterial therapy, the clinician must possess knowledge of the pharmacokinetic and pharmacodynamic properties of commonly used antibacterials and how these parameters may be affected by the constellation of pathophysiological changes occurring during sepsis. Sepsis, and the treatment thereof, increases renal preload and, via capillary permeability, leads to 'third-spacing', both resulting in higher antibacterial clearances. Alternatively, sepsis can induce multiple organ dysfunction, including renal and/or hepatic dysfunction, causing a decrease in antibacterial clearance. Aminoglycosides are concentration-dependent antibacterials and they display an increased volume of distribution (V(d)) in sepsis, resulting in decreased peak serum concentrations. Reduced clearance from renal dysfunction would increase the likelihood of toxicity. Individualised dosing using extended interval dosing, which maximises the peak serum drug concentration (C(max))/minimum inhibitory concentration ratio is recommended. Beta-lactams and carbapenems are time-dependent antibacterials. An increase in V(d) and renal clearance will require increased dosing or administration by continuous infusion. If renal impairment occurs a corresponding dose reduction may be required. Vancomycin displays predominantly time-dependent pharmacodynamic properties and probably requires higher than conventionally recommended doses because of an increased V(d) and clearance during sepsis without organ dysfunction. However, optimal dosing regimens remain unresolved. The poor penetration of vancomycin into solid organs may require alternative therapies when sepsis involves solid organs (e.g. lung). Ciprofloxacin displays largely concentration-dependent kill characteristics, but also exerts some time-dependent effects. The V(d) of ciprofloxacin is not altered with fluid shifts or over time, and thus no alterations of standard doses are required unless renal dysfunction occurs. In order to optimise antibacterial regimens in patients with sepsis, the pathophysiological effects of systemic inflammatory response syndrome need consideration, in conjunction with knowledge of the different kill characteristics of the various antibacterial classes. In conclusion, certain antibacterials can have a very high V(d), therefore leading to a low C(max) and if a high peak is needed, then this would lead to underdosing. The V(d) of certain antibacterials, namely aminoglycosides and vancomycin, changes over time, which means dosing may need to be altered over time. Some patients with serum creatinine values within the normal range can have very high drug clearances, thereby producing low serum drug levels and again leading to underdosing.
Aminoglycosides↗
The use of prophylactic fluconazole in immunocompetent high-risk surgical patients: a meta-analysis.
INTRODUCTION: High-risk surgical patients are at increased risk of fungal infections and candidaemia. Evidence from observational and small randomised controlled studies suggests that prophylactic fluconazole may be effective in reducing fungal infection and mortality. We evaluated the effects of prophylactic fluconazole on the incidence of candidaemia and hospital mortality in immunocompetent high-risk surgical patients. METHODS: Randomised controlled studies involving the use of fluconazole in immunocompetent high-risk surgical patients from the Cochrane Controlled Trial Register (2005, issue 1) and from the EMBASE and MEDLINE databases (1966-30 April 2005), without any language restriction, were included. Two reviewers reviewed the quality of the studies and performed data extraction independently. RESULTS: Seven randomised controlled studies with a total of 814 immunocompetent high-risk surgical patients were considered. The use of prophylactic fluconazole was associated with a reduction in the proportion of patients with candidaemia (relative risk [RR] = 0.21, 95% confidence interval [CI] = 0.06-0.72, P = 0.01; I2 = 0%) and fungal infections other than lower urinary tract infection (RR = 0.39, 95% CI = 0.24-0.65, P = 0.0003; I2 = 0%), but was associated with only a trend towards a reduction in hospital mortality (RR = 0.82, 95% CI = 0.62-1.08, P = 0.15; I2 = 7%). The proportion of patients requiring systemic amphotericin B as a rescue therapy for systemic fungal infection was lower after prophylactic use of fluconazole (RR = 0.35, 95% CI = 0.17-0.72, P = 0.004; I2 = 0%). The proportion of patients colonised with or infected with fluconazole-resistant fungi was not significantly different between the fluconazole group and the placebo group (RR = 0.66, 95% CI = 0.22-1.96, P = 0.46; I2 = 0%). CONCLUSION: The use of prophylactic fluconazole in immunocompetent high-risk surgical patients is associated with a reduced incidence of candidaemia but with only a trend towards a reduction in hospital mortality.
Antifungal Agents↗
Fluid shifts have no influence on ciprofloxacin pharmacokinetics in intensive care patients with intra-abdominal sepsis.
This study aimed to investigate whether fluid shifts alter ciprofloxacin pharmacokinetics in critically ill patients over time. Patients > or = 18 years, with normal renal function, requiring intensive care treatment and parenteral antibiotics were enrolled. Group A (22 patients) included patients with documented intra-abdominal infections. Group B (18 patients) included patients with severe sepsis from other causes. All patients received intravenous ciprofloxacin 400 mg every 8 h infused over 60 min. Eight timed blood specimens were taken on days 0, 2 and 7. Ciprofloxacin plasma concentrations were determined using high performance liquid chromatography. There were no significant differences between the pharmacokinetics of the two groups or over time. Ciprofloxacin pharmacokinetics in critically ill patients do not change over time, and intra-abdominal sepsis does not alter ciprofloxacin pharmacokinetic parameters to a greater degree than sepsis from other causes in critically ill patients.
Adolescent↗
Is the end-game penetration (of the airway)?
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Acetamides↗
Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units.
OBJECTIVE: To determine the population incidence and outcome of severe sepsis occurring in adult patients treated in Australian and New Zealand intensive care units (ICUs), and compare with recent retrospective estimates from the USA and UK. DESIGN: Inception cohort study. SETTING: Twenty-three closed multi-disciplinary ICUs of 21 hospitals (16 tertiary and 5 university affiliated) in Australia and New Zealand. PATIENTS: A total of 5878 consecutive ICU admission episodes. MEASUREMENTS AND RESULTS: Main outcome measures were population-based incidence of severe sepsis, mortality at ICU discharge, mortality at 28 days after onset of severe sepsis, and mortality at hospital discharge. A total of 691 patients, 11.8 (95% confidence intervals 10.9-12.6) per 100 ICU admissions, were diagnosed with 752 episodes of severe sepsis. Site of infection was pulmonary in 50.3% of episodes and abdominal in 19.3% of episodes. The calculated incidence of severe sepsis in adults treated in Australian and New Zealand ICUs is 0.77 (0.76-0.79) per 1000 of population. 26.5% of patients with severe sepsis died in ICU, 32.4% died within 28 days of the diagnosis of severe sepsis and 37.5% died in hospital. CONCLUSION: In this prospective study, 11.8 patients per 100 ICU admissions were diagnosed with severe sepsis and the calculated annual incidence of severe sepsis in adult patients treated in Australian and New Zealand ICUs is 0.77 per 1000 of population. This figure for the population incidence falls in the lower range of recent estimates from retrospective studies in the U.S. and the U.K.
Adult↗
Vancomycin pharmacokinetics in critically ill patients receiving continuous venovenous haemodiafiltration.
AIMS: To investigate the pharmacokinetics of vancomycin in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF), a continuous renal replacement therapy (CRRT) and to see if routine measures approximate vancomycin clearance. METHODS: Pharmacokinetic profiles (15) of initial and steady-state doses of 750 mg twice daily intravenous vancomycin were obtained from blood and ultrafiltrate samples from 10 critically ill patients in the intensive care unit, with acute renal failure on CVVHDF (1 l h(-1) dialysate plus 2 l h(-1) filtration solution; 3 l h(-1) effluent; extracorporeal blood flow 200 ml min(-1)). RESULTS: CVVHDF clearance of vancomycin was 1.8 +/- 0.4 l h(-1) (30 +/- 6.7 ml min(-1)). This was 1.3-7.2 times that reported previously for vancomycin using other forms of CRRT. Total vancomycin body clearance was 2.5 +/- 0.7 l h(-1) (41.7 +/- 11.7 ml min(-1)). The clearance of vancomycin by CVVHDF was 76 +/- 16.5% of the total body clearance. CVVHDF removed approximately half the vancomycin dose during the 12-h period (A(CVVHDF) = 413 mg). The fraction eliminated by all routes was 60%. The sieving coefficient for vancomycin was 0.7 +/- 0.1 and for urea was 0.8 +/- 0.06. CONCLUSIONS: Vancomycin is cleared effectively by CVVHDF. Clearance was faster than other forms of CRRT, therefore doses need to be relatively high. Urea clearance slightly overestimates vancomycin clearance. The administered doses of 750 mg every 12 h were too high and accumulation occurred, as only approximately 60% of a dose was cleared over this period. The maintenance dose required to achieve a target average steady-state plasma concentration of 15 mg l(-1) can be calculated as 450 mg every 12 h.
Adult↗
Cefepime versus cefpirome: the importance of creatinine clearance.
UNLABELLED: Standard dosage recommendations for beta-lactam antibiotics can result in very low drug levels in intensive care (IC) patients without renal dysfunction. We compared the pharmacokinetics of two fourth-generation cephalosporins, cefepime and cefpirome, and examined the relationship of drug clearance (CL) to creatinine clearance (CL(CR)). Two separate but similar pharmacokinetic studies (which used 2 g twice daily for each antibiotic) were conducted. Blood was sampled after an initial and a subsequent antibiotic dose. Drug plasma concentrations were measured, and pharmacokinetic analyses were conducted and compared. The pharmacokinetics of cefepime and cefpirome are similar in IC patients. Any differences in drug CL can largely be attributed to differences in CL(CR). Despite normal plasma creatinine concentrations, 54% of patients' antibiotic concentrations were less than the minimum inhibitory concentration (MIC) (4 mg/L) for >20% of the dosing interval. Thirty-four percent of patients had CL(CR) >144 mL/min (20% higher than the expected maximum of 120 mL/min). Only CL(CR) was an independent predictor of antibiotic CL. Time above MIC was predicted only by CL(CR). Some IC patients have a very large CL(CR), which results in very low levels of studied antibiotics. Either shortening the dosage interval or using continuous infusions would prevent low levels and keep troughs above the MIC for longer periods. In view of the lack of bedside measurement of cephalosporin levels, we suggest that more frequent use be made of CL(CR) to allow prediction of small concentrations clinically. IMPLICATIONS: Some intensive care patients have very large creatinine clearances that result in very low levels of fourth-generation cephalosporins. Serum levels of these antibiotics need to be maintained (time > minimum inhibitory concentration is important). Because routine measurements of cephalosporin levels are generally unavailable, we suggest that more frequent use be made of creatinine clearances to allow prediction of low levels and, hence, alterations in dosing.
Area Under Curve↗
Continuous measurement of cerebral blood flow velocity using transcranial Doppler reveals significant moment-to-moment variability of data in healthy volunteers and in patients with subarachnoid hemorrhage.
OBJECTIVE: The reliability of intermittent transcranial Doppler has not been accepted widely because of problems with interobserver variability and lack of accuracy. The limitations of intermittent transcranial Doppler are thought to be overcome by continuous measurement systems. However, little published data exist on their accuracy, feasibility, and moment-to-moment variability. In this study we aimed to determine the time-related variability of continuous transcranial Doppler signal from volunteers and patients with subarachnoid hemorrhage and to examine the feasibility, ease of use, and quality of data generated from continuous transcranial Doppler for the detection of vasospasm. DESIGN: Prospective observational study. SETTING: Intensive care unit in a tertiary referral center. SUBJECTS: Ten volunteers and eight patients with aneurysmal subarachnoid hemorrhage. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The middle cerebral artery blood flow velocities were recorded continuously from both patients and volunteers. The moment-to-moment variability of continuously recorded data was calculated. There was a wide range of velocity measurements in both volunteers and patients. There was a significant moment-to-moment variability in both volunteers (-31% to 58%) and in patients (-38% to 78%). There was a greater number of observations exceeding 10% moment-to-moment variability in the patient group with regard to systolic and diastolic velocities compared with volunteers (8% vs. 2%, p < .001). There was a trend toward a longer duration of good quality data in volunteers compared with patients (98 +/- 0.5% vs. 96 +/- 9%). CONCLUSIONS: Continuous measurement of cerebral blood flow velocities revealed a significant moment-to-moment variability in both patients and in volunteers, the magnitude of which was greater in the patients. The clinical implications of these findings are discussed.
Adult↗
Manual hyperinflation causes norepinephrine release.
OBJECTIVE: To measure hemodynamics and plasma catecholamines during manual hyperinflation (MHI) in ventilated patients. METHODS: MHI was performed with a Mapleson "C" circuit, 2l-reservoir bag; peak inspiratory pressure was standardized to 35 mL water; and positive expiratory-end pressure of 5 mL water was administered to seven mechanically ventilated patients with septic (6) and cardiogenic (1) shock (67.2 +/- 5.2 years, Acute Physiology Assessment and Chronic Health Evaluation II score 22.1 +/- 3.1). Diastolic (DAP) and mean arterial pressure (MAP), continuous cardiac index, pulmonary artery occlusion pressure, dynamic compliance, plasma norepinephrine and epinephrine, and arterial blood gases were recorded, and systemic vascular resistance index (SVRI) and oxygenation ratio were calculated. RESULTS: There were no significant changes in pulmonary artery occlusion pressure, mean arterial pressure, or PaO2/FiO2. There were significant increases in SVRI (P < .001), DAP (P < .001), dynamic compliance (P < .01), and plasma norepinephrine (P < .001) and a decrease in cardiac index (P < .05) after MHI. CONCLUSIONS: The increases in DAP, SVRI, and plasma norepinephrine suggest a sympathetic vasoconstrictive response during the application of MHI.
Aged↗