Peter Kruger

Antibiotic resistance—what’s dosing got to do with it?

Objective:This review seeks to identify original research articles that link antibiotic dosing and the development of antibiotic resistance for different antibiotic classes. Using this data, we seek to apply pharmacodynamic principles to assist clinical practice for suppressing the emergence of resistance. Concepts such as mutant selection window and mutant prevention concentration will be discussed. Data Sources:PubMed, EMBASE, and the Cochrane Controlled Trial Register. Study Selection:All articles that related antibiotic doses and exposure to the formation of antibiotic resistance were reviewed. Data Synthesis:The escalation of antibiotic resistance continues worldwide, most prominently in patients in intensive care units. Data are emerging from in vitro and in vivo studies that suggest that inappropriately low antibiotic dosing may be contributing to the increasing rate of antibiotic resistance. Fluoroquinolones have widely been researched and publications on other antibiotic classes are emerging. Developing dosing regimens that adhere to pharmacodynamic principles and maximize antibiotic exposure is essential to reduce the increasing rate of antibiotic resistance. Conclusions:Antibiotic dosing must aim to address not only the bacteria isolated, but also the most resistant subpopulation in the colony, to prevent the advent of further resistant infections because of the inadvertent selection pressure of current dosing regimens. This may be achieved by maximizing antibiotic exposure by administering the highest recommended dose to the patient.

A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis

RATIONALE Observational studies link statin therapy with improved outcomes in patients with severe sepsis. OBJECTIVES To test whether atorvastatin therapy affects biologic and clinical outcomes in critically ill patients with severe sepsis. METHODS Phase II, multicenter, prospective, randomized, double-blind, placebo-controlled trial stratified by site and prior statin use. A cohort of 250 critically ill patients (123 statins, 127 placebo) with severe sepsis were administrated either atorvastatin (20 mg daily) or matched placebo. MEASUREMENTS AND MAIN RESULTS There was no difference in IL-6 concentrations (primary end point) between the atorvastatin and placebo groups (P = 0.76) and no interaction between treatment group and time to suggest that the groups behaved differently over time (P = 0.26). Baseline plasma IL-6 was lower among previous statin users (129 [87-191] vs. 244 [187-317] pg/ml; P = 0.01). There was no difference in length of stay, change in Sequential Organ Failure Assessment scores or mortality at intensive care unit discharge, hospital discharge, 28- or 90-day (15% vs. 19%), or adverse effects between the two groups. Cholesterol was lower in patients treated with atorvastatin (2.4 [0.07] vs. 2.6 [0.06] mmol/L; P = 0.006). In the predefined group of 77 prior statin users, those randomized to placebo had a greater 28-day mortality (28% vs. 5%; P = 0.01) compared with those who received atorvastatin. The difference was not statistically significant at 90 days (28% vs. 11%; P = 0.06). CONCLUSIONS Atorvastatin therapy in severe sepsis did not affect IL-6 levels. Prior statin use was associated with a lower baseline IL-6 concentration and continuation of atorvastatin in this cohort was associated with improved survival. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12607000028404).

Continuation of statin therapy in patients with presumed infection: A randomized controlled trial

RATIONALE In patients on prior statin therapy who are hospitalized for acute infections, current literature is unclear on whether statins should be continued during their hospitalization. OBJECTIVES To test the hypothesis that continuation of therapy with statins influences the inflammatory response to infection and that cessation may cause an inflammatory rebound. METHODS Prospective randomized double-blind placebo-controlled trial of atorvastatin (20 mg) or matched placebo in 150 patients on preexisting statin therapy requiring hospitalization for infection. MEASUREMENTS AND MAIN RESULTS The primary end point was progression of sepsis during hospitalization. At baseline, the rate of severe sepsis was 32% in both groups. Compared with baseline, the odds ratio for severe sepsis declined in both groups: 0.43 placebo and 0.5 statins (Day 3) versus 0.14 placebo and 0.12 statins (Day 14). The rate of decline of severe sepsis was similar between the groups (odds ratio 1.17 [0.56-2.47], P = 0.7 Day 3; 0.85 [0.21-3.34], P = 0.8 Day 14). IL-6 and C-reactive protein declined in both groups with no statistically significant difference (P = 0.7 and P = 0.2, respectively). An increase in cholesterol occurred in the placebo group (P < 0.0001). Most patients were not critically ill. Hospital mortality was 6.6%, with no difference between the groups (6 [8%] of 75 statin group; 4 [5.3%] of 75 placebo group; P = 0.75). CONCLUSIONS This study does not support a beneficial role of continuing preexisting statin therapy on sepsis and inflammatory parameters. Cessation of established statin therapy was not associated with an inflammatory rebound. Clinical trial registered at the Australian New Zealand Clinical Trials Registry (ACTRN 12605000756628).

Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis.

PURPOSE The purpose of the study was to determine the effects of Plasma-Lyte 148 (PL) vs 0.9% saline (NS) fluid resuscitation in diabetic ketoacidosis (DKA). METHODS A multicenter retrospective analysis of adults admitted for DKA to the intensive care unit, who received almost exclusively PL or NS infusion up until 12 hours, was performed. RESULTS Nine patients with PL and 14 patients with NS were studied. Median serum bicarbonate correction was higher in the PL vs NS groups at 4 to 6 hours (8.4 vs 1.7 mEq/L) and 6 to 12 hours (12.8 vs 6.2 mEq/L) from baseline (P < .05). Median standard base excess improved by 10.5 vs 4.2 mEq/L at 4 to 6 hours and by 16.0 vs 9.1 mEq/L at 6 to 12 hours in the PL and NS groups, respectively (P < .05). Chloride levels increased significantly in the NS vs PL groups over 24 hours. Potassium levels were lower at 6 to 12 hours in the PL group. Mean arterial blood pressure was higher at 2 to 4 hours in the PL group, whereas cumulative urine output was lower at 4 to 6 hours in the NS group. There were no differences in glycemic control or duration of intensive care unit stay. CONCLUSION Patients with DKA resuscitated with PL instead of NS had faster initial resolution of metabolic acidosis and less hyperchloremia, with a transiently improved blood pressure profile and urine output.

Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance

IntroductionThe aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC (fT>MIC)) in critically ill patients with sepsis receiving intermittent dosing.MethodsTo be eligible for enrolment, critically ill patients with sepsis had to be receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CLCR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT>MIC was calculated for varying MIC and CLCR values.ResultsIn total, 48 patients provided data. Increasing CLCR values were associated with lower trough plasma piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT>MIC would be achieved in only one-third (n = 16) of patients. Mean piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CLCR (r = 0.58, P < 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT>MIC, was noted with increasing CLCR measures.ConclusionsStandard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CLCR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.

Antibiotic dosing in the 'at risk' critically ill patient: Linking pathophysiology with pharmacokinetics/pharmacodynamics in sepsis and trauma patients

BackgroundCritical illness, mediated by trauma or sepsis, can lead to physiological changes that alter the pharmacokinetics of antibiotics and may result in sub-therapeutic concentrations at the sites of infection. The first aim of this project is to identify the clinical characteristics of critically ill patients with significant trauma that have been recently admitted to ICU that may predict the dosing requirements for the antibiotic, cefazolin. The second aim of this is to identify the clinical characteristics of critically ill patients with sepsis that may predict the dosing requirements for the combination antibiotic, piperacillin-tazobactam.Methods/DesignThis is an observational pharmacokinetic study of patients with trauma (cefazolin) or with sepsis (piperacillin-tazobactam). Participants will have samples from blood and urine, collected at different intervals. Patients will also have a microdialysis catheter inserted into subcutaneous tissue to measure interstitial fluid penetration of the antibiotic. Participants will be administered sinistrin, indocyanine green and sodium bromide as well as have cardiac output monitoring performed and tetrapolar bioimpedance to determine physiological changes resulting from pathology. Analysis of samples will be performed using validated liquid chromatography tandem mass-spectrometry. Pharmacokinetic analysis will be performed using non-linear mixed effects modeling to determine individual and population pharmacokinetic parameters of antibiotics.DiscussionThe study will describe cefazolin and piperacillin-tazobactam concentrations in plasma and the interstitial fluid of tissues in trauma and sepsis patients respectively. The results of this study will guide clinicians to effectively dose these antibiotics in order to maximize the concentration of antibiotics in the interstitial fluid of tissues.

Cavernous sinus thrombosis and meningitis from community-acquired methicillin-resistant Staphylococcus aureus infection

Septic cavernous sinus thrombosis is an uncommon clinical syndrome with a high morbidity and mortality. The commonest bacterial pathogen is Staphylococcus aureus. We describe the study of a patient with cavernous sinus thrombosis and meningitis caused by community‐acquired methicillin‐resistant S. aureus (CA‐MRSA) infection. The isolate was genotyped as the ST93 (Queensland) clone of CA‐MRSA and carried the Panton‐Valentine leucocidin genes. Cure was obtained following prolonged antimicrobial therapy with vancomycin, rifampicin, cotrimoxazole and linezolid. Given the high morbidity and mortality of cavernous sinus thrombosis and the worldwide recent emergence of CA‐MRSA, clinicians treating patients with this infection should consider early empirical coverage for CA‐MRSA with an antimicrobial agent, such as vancomycin or linezolid, particularly in the presence of suspected facial staphylococcal skin infections. If vancomycin is used, we emphasize that high doses may be required to achieve even low levels in the cerebrospinal fluid.

Plasma and target-site subcutaneous tissue population pharmacokinetics and dosing simulations of cefazolin in post-trauma critically ill patients

OBJECTIVES The objective of this study was to describe the population pharmacokinetics of cefazolin in plasma and the interstitial fluid of subcutaneous tissue of post-trauma critically ill patients and provide clinically relevant dosing recommendations that result in optimal concentrations at the target site. PATIENTS AND METHODS This was a pharmacokinetic study in a tertiary referral ICU. We recruited 30 post-trauma critically ill adult patients and collected serial total and unbound plasma cefazolin concentrations. Interstitial fluid concentrations were determined using in vivo microdialysis. Population pharmacokinetic analysis and Monte Carlo simulations were undertaken with Pmetrics(®). Fractional target attainment against an MIC distribution for Staphylococcus aureus isolates was calculated. RESULTS The mean (SD) age, weight, APACHE II score and CLCR were 37.0 (14.1) years, 86.8 (22.7) kg, 16.9 (5.3) and 163 (44) mL/min, respectively. A three-compartment linear population pharmacokinetic model was most appropriate. Covariates included in the model were CLCR on drug clearance and serum albumin concentration and body weight on the volume of the central compartment. The fractional target attainment for a 1 g intravenous 8-hourly dose for a CLCR of 50 mL/min was 88%, whereas for a patient with a CLCR of 215 mL/min, a dose of 2 g 6-hourly achieved 84% fractional target attainment. CONCLUSIONS Clinicians should be mindful of the effects of elevated CLCR and serum albumin concentrations on dosing requirements for post-trauma critically ill patients.

Plasma acetate, gluconate and interleukin-6 profiles during and after cardiopulmonary bypass: a comparison of Plasma-Lyte 148 with a bicarbonate-balanced solution

IntroductionAs even small concentrations of acetate in the plasma result in pro-inflammatory and cardiotoxic effects, it has been removed from renal replacement fluids. However, Plasma-Lyte 148 (Plasma-Lyte), an electrolyte replacement solution containing acetate plus gluconate is a common circuit prime for cardio-pulmonary bypass (CPB). No published data exist on the peak plasma acetate and gluconate concentrations resulting from the use of Plasma-Lyte 148 during CPB.MethodsThirty adult patients were systematically allocated 1:1 to CPB prime with either bicarbonate-balanced fluid (24 mmol/L bicarbonate) or Plasma-Lyte 148. Arterial blood acetate, gluconate and interleukin-6 (IL-6) levels were measured immediately before CPB (T1), three minutes after CPB commencement (T2), immediately before CPB separation (T3), and four hours post separation (T4).ResultsAcetate concentrations (normal 0.04 to 0.07 mmol/L) became markedly elevated at T2, where the Plasma-Lyte group (median 3.69, range (2.46 to 8.55)) exceeded the bicarbonate group (0.16 (0.02 to 3.49), P < 0.0005). At T3, levels had declined but the differential pattern remained apparent (Plasma-Lyte 0.35 (0.00 to 1.84) versus bicarbonate 0.17 (0.00 to 0.81)). Normal circulating acetate concentrations were not restored until T4. Similar gluconate concentration profiles and inter-group differences were seen, with a slower T3 decay. IL-6 increased across CPB, peaking at T4, with no clear difference between groups.ConclusionsUse of acetate containing prime solutions result in supraphysiological plasma concentrations of acetate. The use of acetate-free prime fluid in CPB significantly reduced but did not eliminate large acetate surges in cardiac surgical patients. Complete elimination of acetate surges would require the use of acetate free bolus fluids and cardioplegia solutions.Trial registrationAustralia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000267055

Indocyanine green elimination: a comparison of the LiMON and serial blood sampling methods.

Background:  Indocyanine green (ICG) elimination is a test widely used to evaluate hepatic functional reserve in patients being assessed for hepatic resection. This study compares a non‐invasive liver function monitoring system, the LiMON (Pulsion Medical Systems, Munich, Germany), with serial blood sampling methods.