Evaluation of Vancomycin in Combination with Piperacillin-Tazobactam or Oxacillin against Clinical Methicillin-Resistant Staphylococcus aureus Isolates and Vancomycin-Intermediate S. aureus Isolates In Vitro

Vancomycin with piperacillin-tazobactam is used as empirical therapy for critically ill patients. Studies of this combination against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) are limited, but β-lactams in combination with vancomycin have shown synergistic activity against MRSA and VISA. The goal of this study was to evaluate whether piperacillin-tazobactam and vancomycin were synergistic against MRSA and VISA in vitro. Bloodstream MRSA (n = 20) and VISA (n = 4) strains were selected. In vitro antimicrobial activities of piperacillin-tazobactam and oxacillin were evaluated by disk diffusion, and MICs were determined by Etest using Muller-Hinton agar with and without vancomycin at one-half the MIC. Time-kill studies evaluated 14 MRSA and all 4 VISA isolates using piperacillin-tazobactam at 300/35 mg/liter or oxacillin at 40 mg/liter alone and with vancomycin at one-half the MIC. Mean zones of inhibition for piperacillin-tazobactam and oxacillin increased with vancomycin against MRSA and VISA (P < 0.001 for all), and the MIC₉₀ decreased with vancomycin against MRSA and VISA to values meeting susceptibility criteria for S. aureus (P < 0.001 for both antibiotics against MRSA). In MRSA time-kill studies, the mean 24-h reductions in inoculum for piperacillin-tazobactam, piperacillin-tazobactam with vancomycin, and oxacillin with vancomycin were 3.53, 3.69, and 2.62 log₁₀ CFU/ml, respectively. The mean 24-h reductions in VISA inoculum for piperacillin-tazobactam, piperacillin-tazobactam with vancomycin, and oxacillin with vancomycin were 2.85, 2.93, and 3.45 log₁₀ CFU/ml, respectively. Vancomycin with piperacillin-tazobactam or oxacillin demonstrated synergistic activity against MRSA and VISA. The clinical implications of these combinations against MRSA and VISA should be investigated.     

Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates

National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-h area under the concentration-time curve (AUC_0–24)-to-MIC ratio of >400. The range of vancomycin trough concentrations that best predicts an AUC_0–24 of >400 in neonates is not known. This understanding would help clarify target trough concentrations in neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine the relationships between trough and AUC_0–24 in the study neonates. Monte Carlo simulations were performed to examine the effect of dose, postmenstrual age (PMA), and serum creatinine level on trough and AUC_0–24 achievement. A total of 1,702 vancomycin concentrations from 249 neonates were available for analysis. The median (interquartile range) PMA was 39 weeks (32 to 42 weeks) and weight was 2.9 kg (1.6 to 3.7 kg). Vancomycin clearance was predicted by weight, PMA, and serum creatinine level. At a trough of 10 mg/liter, 89% of the study neonates had an AUC_0–24 of >400. Monte Carlo simulations demonstrated that troughs ranging from 7 to 11 mg/liter were highly predictive of an AUC_0–24 of >400 across a range of PMA, serum creatinine levels, and vancomycin doses. However, a trough of ≥10 mg/liter was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs of >20 mg/liter. A vancomycin trough of ∼10 mg/liter is likely adequate for most neonates with invasive MRSA infections based on considerations of the AUC_0–24. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses is difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization.     

In Vitro Pharmacodynamics of Human Simulated Exposures of Telavancin against Methicillin-Susceptible and -Resistant Staphylococcus aureus with and without Prior Vancomycin Exposure

Telavancin is a lipoglycopeptide with potent activity against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). The activity of telavancin against MRSA and MSSA after prior vancomycin exposure was studied in an in vitro pharmacodynamic model. Two clinical MRSA and two MSSA isolates, all with vancomycin MICs of 2 μg/ml, were subjected to humanized free drug exposures of vancomycin at 1 g every 12 h (q12h) for 96 h, telavancin at 750 mg q24h for 96 h, and vancomycin at 1 g q12h for 72 h followed by telavancin at 750 mg q24h for 48 h (120 h total). The microbiological responses were measured by changes from 0 h in log₁₀ CFU/ml at the end of experiments and area under the bacterial killing and regrowth curves over 96 h (AUBC₀₋₉₆). The control isolates grew to 8.8 ± 0.3 log₁₀ CFU/ml. Initially, all regimens caused −4.5 ± 0.9 reductions in log₁₀ CFU/ml by 48 h followed by slight regrowth over the following 48 to 72 h. After 96 h, vancomycin and telavancin achieved −3.7 ± 0.9 and −3.8 ± 0.8 log₁₀ CFU/ml changes from baseline, respectively (P = 0.74). Sequential exposure to telavancin after vancomycin did not result in additional CFU reductions or increases, with ultimate log₁₀ CFU/ml reductions of −4.3 ± 1.1 at 96 h and −4.2 ± 1.3 at 120 h (P > 0.05 for all comparisons at 96 h). The AUBC_0–96 was significantly smaller for the regimen of telavancin for 96 h than for the regimens of vancomycin for 96 h and vancomycin followed by telavancin (P ≤ 0.04). No resistance was observed throughout the experiment. Against these MRSA and MSSA isolates with vancomycin MICs of 2 μg/ml, telavancin was comparable with vancomycin and its activity was unaffected by prior vancomycin exposure.     

Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin

There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus aureus (MRSA) infections, with vancomycin MICs at the high end of the CLSI susceptibility range. Despite this growing concern, there are limited clinical data to support this notion. To better elucidate this, a retrospective cohort study was conducted among patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and May 2007. The inclusion criteria were as follows: at least 18 years old, nonneutropenic, with an MRSA culture that met the CDC criteria for bloodstream infection, had received vancomycin therapy within 48 h of the index blood culture, and survived >24 h after vancomycin administration. Failure was defined as 30-day mortality, bacteremia ≥10 days on vancomycin therapy, or a recurrence of MRSA bacteremia within 60 days of vancomycin discontinuation. Classification and regression tree (CART) analysis identified the vancomycin MIC breakpoint associated with an increased probability of failure. During the study period, 92 patients met the inclusion criteria. The vancomycin MIC breakpoint derived by CART analysis was ≥1.5 mg/liter. The 66 patients with vancomycin MICs of ≥1.5 mg/liter had a 2.4-fold increase in failure compared to patients with MICs of ≤1.0 mg/liter (36.4% and 15.4%, respectively; P = 0.049). In the Poisson regression, a vancomycin MIC of ≥1.5 mg/liter was independently associated with failure (adjusted risk ratio, 2.6; 95% confidence interval, 1.3 to 5.4; P = 0.01). These data strongly suggest that patients with MRSA bloodstream infections with vancomycin MICs of ≥1.5 mg/liter respond poorly to vancomycin. Alternative anti-MRSA therapies should be considered for these patients.     

Efficacy of Fosfomycin Compared to Vancomycin in Treatment of Implant-Associated Chronic Methicillin-Resistant Staphylococcus aureus Osteomyelitis in Rats

Fosfomycin monotherapy was compared to therapy with vancomycin for the treatment of implant-associated methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis in an experimental rat model. The proximal tibiae were inoculated with 15 μl of a suspension containing 1 × 10⁸ to 5 × 10⁸ CFU/ml of a clinical isolate of MRSA with simultaneous insertion of a titanium wire. Four weeks later, treatment was started for 28 days with either 50 mg/kg of body weight vancomycin intraperitoneally twice daily (n = 11) or 75 mg/kg fosfomycin intraperitoneally once daily (n = 10). Eleven animals were left untreated. After treatment, quantitative cultures from bone were found to be positive for MRSA in all animals in the untreated group (median, 3.29 × 10⁶ CFU/g of bone) and the vancomycin group (median, 3.03 × 10⁵ CFU/g of bone). In the fosfomycin group, MRSA was detectable in 2 out of 10 (20%) animals (3.42 × 10² and 1.51 × 10³ CFU/g of bone). Vancomycin was superior to the no-drug control (P = 0.002), and fosfomycin was superior to the no-drug control and vancomycin (P < 0.001). The cultures from the wires were positive in all untreated animals (median, 2.5 × 10³ CFU/implant), in 10 animals in the vancomycin group (median, 1.15 × 10³ CFU/implant), and negative in all animals in the fosfomycin group. Based on the bacterial counts from the implants, vancomycin was not superior to the no-drug control (P = 0.324), and fosfomycin was superior to the no-drug control and vancomycin (P < 0.001). No emergence of resistance was observed. In conclusion, it was demonstrated that fosfomycin monotherapy is highly effective for the treatment of experimental implant-associated MRSA osteomyelitis.     

Decreasing the time to achieve therapeutic vancomycin concentrations in critically ill patients: developing and testing of a dosing nomogram

Introduction

Achievement of optimal vancomycin exposure is crucial to improve the management of patients with life-threatening infections caused by susceptible Gram-positive bacteria and is of particular concern in patients with augmented renal clearance (ARC). The aim of this study was to develop a dosing nomogram for the administration of vancomycin by continuous infusion for the first 24 hours of therapy based on the measured urinary creatinine clearance (8 h CL_CR).

Methods

This single-center study included all critically ill patients treated with vancomycin over a 13-month period (group 1), in which we retrospectively assessed the correlation between vancomycin clearance and 8 h CL_CR. This data was used to develop a formula for optimised drug dosing. The efficiency of this formula was prospectively evaluated in a second cohort of 25 consecutive critically ill patients (group 2). Vancomycin serum concentrations between 20 to 30 mg/L were considered adequate. ARC was defined as 8 h CL_CR more than 130 ml/min/1.73 m².

Results

The incidence of ARC was 36% (n = 29/79) and 40% (10/25) in group 1 (n = 79) and 2 (n = 25), respectively. The mean serum vancomycin concentration on day 1 was 21.5 (6.4) and 24.5 (5.2) mg/L, for both groups respectively. On the treatment day, vancomycin plasma clearance was 5.12 (1.9) L/h in group 1 and correlated significantly with the 8 h CL_CR (r² = 0.66; P <0.001). The achievement of adequate vancomycin serum concentrations in group 2 was 84% (n = 21/25) versus 51% (n = 40/79) – P <0.005.

Conclusions

This new vancomycin nomogram enabled the achievement of adequate serum concentrations in 84% of the patients on the first day of treatment.     

Ceftaroline Increases Membrane Binding and Enhances the Activity of Daptomycin against Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model

New antimicrobial agents and novel combination therapies are needed to treat serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to daptomycin and vancomycin. The purpose of this study was to evaluate the combination of ceftaroline plus daptomycin or vancomycin in an in vitro pharmacokinetic/pharmacodynamic model. Simulations of ceftaroline-fosamil at 600 mg per kg of body weight every 8 h (q8h) (maximum free-drug concentration in serum [fC_max], 15.2 mg/liter; half-life [t_1/2], 2.3 h), daptomycin at 10 mg/kg/day (fC_max, 11.3 mg/liter; t_1/2, 8 h), vancomycin at 2 g q12h (fC_max, 30 mg/liter; t_1/2, 6 h), ceftaroline plus daptomycin, and ceftaroline plus vancomycin were evaluated against a clinical, isogenic MRSA strain pair: D592 (daptomycin susceptible and heterogeneous vancomycin intermediate) and D712 (daptomycin nonsusceptible and vancomycin intermediate) in a one-compartment in vitro pharmacokinetic/pharmacodynamic model over 96 h. Therapeutic enhancement of combinations was defined as ≥2 log₁₀ CFU/ml reduction over the most active single agent. The effect of ceftaroline on the membrane charge, cell wall thickness, susceptibility to killing by the human cathelicidin LL37, and daptomycin binding were evaluated. Therapeutic enhancement was observed with daptomycin plus ceftaroline in both strains and vancomycin plus ceftaroline against D592. Ceftaroline exposure enhanced daptomycin-induced depolarization (81.7% versus 72.3%; P = 0.03) and killing by cathelicidin LL37 (P < 0.01) and reduced cell wall thickness (P < 0.001). Fluorescence-labeled daptomycin was bound over 7-fold more in ceftaroline-exposed cells. Whole-genome sequencing and mutation analysis of these strains indicated that change in daptomycin susceptibility is related to an fmtC (mprF) mutation. The combination of daptomycin plus ceftaroline appears to be potent, with rapid and sustained bactericidal activity against both daptomycin-susceptible and -nonsusceptible strains of MRSA.     

In Vitro Pharmacodynamics of Human Simulated Exposures of Ceftaroline and Daptomycin against MRSA,hVISA, and VISA with and without Prior Vancomycin Exposure

The effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistant Staphylococcus aureus (MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-h in vitro pharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediate S. aureus (hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log₁₀ CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log₁₀ CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log₁₀ CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log₁₀ CFU was largest for sequential therapy with vancomycin followed by ceftaroline (−5.22 ± 1.2, P = 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (−3.60 ± 0.6, P = 0.037 versus daptomycin), compared with daptomycin (−2.24 ± 1.0), vancomycin (−1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (−1.32 ± 1.0, P > 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.     

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

The current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults with Staphylococcus aureus infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%; P = 0.0001) and 14% (7 to 19%; P < 0.0001), respectively. In contrast, using the full model as a Bayesian prior with trough-only data allowed 97% (93 to 102%; P = 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of ≥400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter.     

Pharmacodynamics of a Simulated Single 1,200-Milligram Dose of Oritavancin in an In Vitro Pharmacokinetic/Pharmacodynamic Model of Methicillin-Resistant Staphylococcus aureus Infection

The safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitro pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of oritavancin to once-daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistant Staphylococcus aureus (MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC_0-24), 48 h (AUBKC_0-48), and 72 h (AUBKC_0-72). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC_0-24s for the three MRSA strains than with vancomycin (P < 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC_0-48 and AUBKC_0-72 against one MRSA strain and a lower AUBKC_0-48 for another strain than did vancomycin exposure (P < 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC_0-48 and AUBKC_0-72 for one of the MRSA isolates than did vancomycin exposure (P < 0.05). Lower AUBKC_0-24s for two of the MRSA strains (P < 0.05) were obtained with oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an in vitro pharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.     

Evaluation of sulfobutylether-β-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy

IntroductionIntravenous (IV) voriconazole is not recommended in patients with creatinine clearance <50 ml/min to avoid potentially toxic accumulation of sulfobutylether-β-cyclodextrin (SBECD). The purpose of this study was to evaluate the pharmacokinetics of SBECD, voriconazole, and voriconazole N-oxide in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to determine if CRRT removes SBECD sufficiently to allow for the use of IV voriconazole without significant risk of SBECD accumulation.MethodsThis prospective, open-label pharmacokinetic study enrolled patients >18 years old receiving IV voriconazole for a known or suspected invasive fungal infection while undergoing CRRT. Serial blood and effluent samples were collected on days 1, 3, 5, 7, and every 3 to 5 days thereafter. SBECD, voriconazole, and voriconazole N-oxide plasma and effluent concentrations were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic, pharmacodynamic, and pharmacogenetic analyses were conducted.ResultsTen patients (mean ± standard deviation (SD)) 53 ± 11 years old, 50% male, 81 ± 14 kg, with Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores of 31.5 ± 3.8 were evaluated. All patients underwent continuous venovenous hemofiltration (CVVH) with a median predilution replacement fluid rate of 36 (interquartile range (IQR) 32 to 37) ml/kg/hr and total ultrafiltration rate of 38 (IQR 34 to 39) ml/kg/hr. Mean ± SD voriconazole and SBECD dosages administered were 8.1 ± 2.1 mg/kg/day and 129 ± 33 mg/kg/day, respectively. Voriconazole plasma trough concentrations were >1 mg/L in all patients with CVVH accounting for only 15% of the total body clearance. CVVH accounted for 86% of the total body clearance of SBECD with the majority of the dose being recovered in the effluent. Minimal increases in dose normalized SBECD area under the concentration-time curve from 0 to 12 hours (AUC0-12) (4,484 ± 4,368 to 4,553 ± 2,880 mg*hr/L; P = 0.97) were observed after study day 1.ConclusionsCVVH effectively removed SBECD at a rate similar to the ultrafiltration rate. Voriconazole clearance by CVVH was not clinically significant. Standard dosages of IV voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01101386","term_id":"NCT01101386"}}NCT01101386. Registered 6 April 2010.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0753-8) contains supplementary material, which is available to authorized users.     

Hypophosphatemia during continuous veno-venous hemofiltration is associated with mortality in critically ill patients with acute kidney injury

Introduction

The primary aim of this study was to determine whether hypophosphatemia during continuous veno-venous hemofiltration (CVVH) is associated with the global outcome of critically ill patients with acute kidney injury (AKI).

Methods

760 patients diagnosed with AKI and had received CVVH therapy were retrospectively recruited. Death during the 28-day period and survival at 28 days after initiation of CVVH were used as endpoints. Demographic and clinical data including serum phosphorus levels were recorded along with clinical outcome. Hypophosphatemia was defined according to the colorimetric method as serum phosphorus levels < 0.81 mmol/L (2.5 mg/dL), and severe hypophosphatemia was defined as serum phosphorus levels < 0.32 mmol/L (1 mg/dL). The ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was calculated to reflect the persistence of hypophosphatemia.

Results

The Cox proportional hazard survival model analysis indicated that the incidence of hypophosphatemia or even severe hypophosphatemia was not associated with 28-day mortality independently (p = 0.700). Further analysis with the sub-cohort of patients who had developed hypophosphatemia during the CVVH therapy period indicated that the mean ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was 0.58, and the ratio independently associated with the global outcome. Compared with the patients with low ratio (< 0.58), those with high ratio (≥ 0.58) conferred a 1.451-fold increase in 28-day mortality rate (95% CI 1.103–1.910, p = 0.008).

Conclusions

Hypophosphatemia during CVVH associated with the global clinical outcome of critically ill patients with AKI. The ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was independently associated with the 28-day mortality, and high ratio conferred higher mortality rate.     

Blood hemoperfusion with resin adsorption combined continuous veno-venous hemofiltration for patients with multiple organ dysfunction syndrome

BACKGROUND:

Blood hemoperfusion with resin adsorption can clean larger molecules that exceed the molecular weight cutoff of combined continuous veno-venous hemofiltration (CVVH). Hence blood hemoperfusion with resin adsorption combined CVVH (HP+CVVH) has higher ability of mediator clearance, and can improve clinical outcomes in theory. This study aimed to investigate the effect of blood hemoperfusion with resin adsorption combined continuous veno-venous hemofiltration (HP+CVVH) on plasm cytokines like TNF-α, IL-1β, IL-6, cellular immunity and prognosis in patients with multiple organ dysfunction syndrome (MODS).

METHODS:

This was a prospective, randomized clinical trial. A total of 30 patients who had been diagnosed with MODS were enrolled in this study. Patients were randomly allocated to routine treatment+HP+CVVH group (treatment group) and routine treatment+only CVVH group (control group). In the treatment group, patients received blood hemoperfusion with resin adsorption for 2 hours, and then received CVVH for 10 hours every day. In the control group, patients received CVVH for 12 hours only every day. The patients in the two groups received blood purification therapy for three days. The plasma of patients in the treatment group was obtained at 0, 2, 12, 24, 26, 36, 48, 50, 60 hours, 5th day, 7th day and 10th day, respectively. The plasma of patients in the control group was obtained at 0, 12, 24, 36, 48, 60 hours, 5th day, 7th day and 10th day, respectively. APACHE II score, T-lymphocytes subpopulations, blood lactate acid concentration, heart rate, breathing rate, and oxygenation index were observed.

RESULTS:

Plasma cytokines like TNF-α, IL-1β, IL-6 decreased markedly after HP (P<0.01); T-lymphocytes subpopulations CD3+, CD4+, CD8+, CD4+/CD8+ increased after HP+CVVH or only CVVH. The plasma concentrations of TNF-α, IL-1β and IL-6 in the two groups were not markedly different at 12, 36, and 50 hours. But on the 5th day, the plasma concentrations of TNF-α, IL-1β and IL-6 in the treatment group were lower than those in the control group (P<0.05). On the 28th day, 5 patients died in the treatment group, and 6 patients in the control group.

CONCLUSIONS:

Both HP+CVVH and CVVH can clean plasma cytokines like TNF-α, IL-1β, and IL-6, and improve cellular immunity and clinical symptoms and signs of patients. Compared with only CVVH, the plasma concentrations of TNF-α, IL-1β and IL-6 were lower on the 5th day, and patients have an increased survival rate on the 28 day in the HP+CVVH group.KEY WORDS: Hemoperfusion with resin adsorption, Continuous veno-venous hemofiltration, Multiple organ dysfunction syndrome, Cytokines     

The plasma level and biomarker value of neutrophil gelatinase-associated lipocalin in critically ill patients with acute kidney injury are not affected by continuous venovenous hemofiltration and anticoagulation applied

Introduction

Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI), and levels reflect severity of disease in critically ill patients. However, continuous venovenous hemofiltration (CVVH) may affect plasma levels by clearance or release of NGAL by activated neutrophils in the filter, dependent on the anticoagulation regimen applied. We therefore studied handling of NGAL by CVVH in patients with AKI.

Methods

Immediately before initiation of CVVH, prefilter blood was drawn. After 10, 60, 180, and 720 minutes of CVVH, samples were collected from pre- and postfilter (in- and outlet) blood and ultrafiltrate. CVVH with the following anticoagulation regimens was studied: no anticoagulation in case of a high bleeding tendency (n = 13), unfractionated heparin (n = 8), or trisodium citrate (n = 21). NGAL levels were determined with enzyme-linked immunosorbent assay (ELISA).

Results

Concentrations of NGAL at inlet and outlet were similar, and concentrations did not change over time in any of the anticoagulation groups; thus no net removal or production of NGAL occurred. Concentrations of NGAL at inlet correlated with disease severity at initiation of CVVH and at the end of a CVVH run. Concentrations of NGAL in the ultrafiltrate were lower with citrate-based CVVH (P = 0.03) and decreased over time, irrespective of anticoagulation administered (P < 0.001). The sieving coefficient and clearance of NGAL were low and decreased over time (P < 0.001).

Conclusions

The plasma level and biomarker value of NGAL in critically ill patients with AKI are not affected by CVVH, because clearance by the filter was low. Furthermore, no evidence exists for intrafilter release of NGAL by neutrophils, irrespective of the anticoagulation method applied.     

Efficacy of Teicoplanin and Autoradiographic Diffusion Pattern of [14C]Teicoplanin in Experimental Staphylococcus aureus Infection of Joint Prostheses

Prosthesis infections are difficult to cure. Infection with methicillin-resistant staphylococci is becoming more common in patients with orthopedic implants. Using a recently developed model of methicillin-resistant Staphylococcus aureus (MRSA) infection of a knee prosthesis, we compared the efficacies of teicoplanin and vancomycin. [¹⁴C]teicoplanin diffusion in this model was also studied by autoradiography. A partial knee replacement was performed with a silicone implant fitting into the intramedullary canal of the tibia, and 10⁷ CFU of MRSA was injected into the knee. Treatment with teicoplanin or vancomycin (20 or 60 mg/kg of body weight, respectively, given intramuscularly twice daily) was started 7 days after inoculation and was continued for 7 days. The teicoplanin and vancomycin MICs for MRSA were 1 μg/ml. Mean peak and trough levels in serum were 39.1 and 23.5 μg/ml, respectively, for teicoplanin and 34.4 and 18.5 μg/ml, respectively, for vancomycin. Fifteen days after the end of therapy, the animals were killed and their tibias were removed, pulverized, and quantitatively cultured. Teicoplanin and vancomycin significantly reduced (P < 0.05) the bacterial density (2.7 ± 1.3 and 3.3 ± 1.6 log₁₀ CFU/g of bone, respectively) compared to those for the controls (5.04 ± 1.4 log₁₀ CFU/g of bone). The bacterial covents of teicoplanin- and vancomycin-treated rabbits were comparable. The [¹⁴C]teicoplanin autoradiographic diffusion patterns in rabbits with prostheses, two of which were uninfected and two of which were infected, were studied 15 days after inoculation. Sixty minutes after the end of an infusion of 250 μCi of [¹⁴C]teicoplanin, autoradiography showed that in the infected animals, the highest levels of radioactivity were located around the prosthesis and in the periosteum, bone marrow, and trabecular bone. Radioactivity was less intense in epiphyseal disk cartilage, femoral cartilage, articular ligaments, and muscles and was weak in compact bone. A similar distribution pattern was seen in uninfected rabbits. Thus, teicoplanin may represent an effective alternative therapy for the treatment of these infections.     

Single-Dose Pharmacokinetics of Meropenem during Continuous Venovenous Hemofiltration

The pharmacokinetic properties of meropenem were investigated in nine critically ill patients treated by continuous venovenous hemofiltration (CVVH). All patients received one dose of 1 g of meropenem intravenously. High-flux polysulfone membranes were used as dialyzers. Meropenem levels were measured in plasma and ultrafiltrate by high-performance liquid chromatography. The total body clearance and elimination half-life were 143.7 ± 18.6 ml/min and 2.46 ± 0.41 h, respectively. The post- to prehemofiltration ratio of meropenem was 0.24 ± 0.06. Peak plasma drug concentrations measured 60 min postinfusion were 28.1 ± 2.7 μg/ml, and trough levels after 6 h of CVVH were 6.6 ± 1.5 μg/ml. The calculated total daily meropenem requirement in these patients with acute renal failure and undergoing CVVH was 2,482 ± 321 mg. Based on these data, we conclude that patients with severe infections who are undergoing CVVH can be treated effectively with 1 g of meropenem every 8 h.     

Does contemporary vancomycin dosing achieve therapeutic targets in a heterogeneous clinical cohort of critically ill patients? Data from the multinational DALI study

Introduction

The objective of this study was to describe the pharmacokinetics of vancomycin in ICU patients and to examine whether contemporary antibiotic dosing results in concentrations that have been associated with favourable response.

Methods

The Defining Antibiotic Levels in Intensive Care (DALI) study was a prospective, multicentre pharmacokinetic point-prevalence study. Antibiotic dosing was as per the treating clinician either by intermittent bolus or continuous infusion. Target trough concentration was defined as ≥15 mg/L and target pharmacodynamic index was defined as an area under the concentration-time curve over a 24-hour period divided by the minimum inhibitory concentration of the suspected bacteria (AUC_0–24/MIC ratio) >400 (assuming MIC ≤1 mg/L).

Results

Data of 42 patients from 26 ICUs were eligible for analysis. A total of 24 patients received vancomycin by continuous infusion (57%). Daily dosage of vancomycin was 27 mg/kg (interquartile range (IQR) 18 to 32), and not different between patients receiving intermittent or continuous infusion. Trough concentrations were highly variable (median 27, IQR 8 to 23 mg/L). Target trough concentrations were achieved in 57% of patients, but more frequently in patients receiving continuous infusion (71% versus 39%; P = 0.038). Also the target AUC_0–24/MIC ratio was reached more frequently in patients receiving continuous infusion (88% versus 50%; P = 0.008). Multivariable logistic regression analysis with adjustment by the propensity score could not confirm continuous infusion as an independent predictor of an AUC_0–24/MIC >400 (odds ratio (OR) 1.65, 95% confidence interval (CI) 0.2 to 12.0) or a C_min ≥15 mg/L (OR 1.8, 95% CI 0.4 to 8.5).

Conclusions

This study demonstrated large interindividual variability in vancomycin pharmacokinetic and pharmacodynamic target attainment in ICU patients. These data suggests that a re-evaluation of current vancomycin dosing recommendations in critically ill patients is needed to more rapidly and consistently achieve sufficient vancomycin exposure.     

Clinical Outcomes in Patients with Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Bloodstream Infection

The prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) infections varies in the literature, a problem complicated by the lack of routine screening procedures; however, limited data suggest that hVISA has been associated with persistent bloodstream infections (BSI) and vancomycin failure, yet these studies have been confounded by design issues. We conducted this study to compare the characteristics of patients with BSI caused by hVISA with those with vancomycin-susceptible Staphylococcus aureus (VSSA) treated with vancomycin. This retrospective, multicenter matched (1:1) cohort study compared the clinical characteristics and outcomes of hVISA and VSSA. Patients with hVISA methicillin-resistant Staphylococcus aureus (MRSA) BSI from 2004 to 2012 were matched to VSSA-MRSA BSI patients. The primary outcome was failure of vancomycin treatment, defined as a composite of persistent bacteremia (≥7 days), persistent signs and symptoms, change of MRSA antibiotic, recurrent BSI, or MRSA-related mortality. We identified 122 matched cases. The overall vancomycin failure rate was 57% (82% hVISA versus 33% VSSA; P < 0.001). The individual components of failure in hVISA versus VSSA were persistent bacteremia, 59% versus 21% (P < 0.001); change in MRSA therapy, 54% versus 25% (P = 0.001); MRSA-related mortality, 21% versus 10% (P = 0.081); and recurrence of BSI, 26% versus 2% (P < 0.001). Using logistic regression analysis and adjusting for covariates, hVISA (adjusted odds ratio [aOR], 11.1; 95% confidence interval [CI], 4.3 to 28.7) and intensive care unit (ICU) admission (aOR, 4.5; 95% CI, 1.8 to 11.6) were still independently associated with vancomycin failure. Relative to VSSA BSI, patients with hVISA were more likely to experience failure of vancomycin treatment, including persistent bacteremia and recurrence. Our results indicate that hVISA was responsible for considerable morbidity.     

Serum cystatin C predicts vancomycin trough levels better than serum creatinine in hospitalized patients: a cohort study

Introduction

Serum cystatin C can improve glomerular filtration rate (GFR) estimation over creatinine alone, but whether this translates into clinically relevant improvements in drug dosing is unclear.

Methods

This prospective cohort study enrolled adults receiving scheduled intravenous vancomycin while hospitalized at the Mayo Clinic in 2012. Vancomycin dosing was based on weight, serum creatinine with the Cockcroft-Gault equation, and clinical judgment. Cystatin C was later assayed from the stored serum used for the creatinine-based dosing. Vancomycin trough prediction models were developed by using factors available at therapy initiation. Residuals from each model were used to predict the proportion of patients who would have achieved the target trough with the model compared with that observed with usual care.

Results

Of 173 patients enrolled, only 35 (20%) had a trough vancomycin level within their target range (10 to 15 mg/L or 15 to 20 mg/L). Cystatin C-inclusive models better predicted vancomycin troughs than models based upon serum creatinine alone, although both were an improvement over usual care. The optimal model used estimated GFR by the Chronic Kidney Disease Epidemiology Collaborative (CKD-EPI) _{creatinine-cystatin C} equation (R² = 0.580). This model is expected to yield 54% (95% confidence interval 45% to 61%) target trough attainment (P <0.001 compared with the 20% with usual care).

Conclusions

Vancomycin dosing based on standard care with Cockcroft-Gault creatinine clearance yielded poor trough achievement. The developed dosing model with estimated GFR from CKD-EPI_{creatinine-cystatin C} could yield a 2.5-fold increase in target trough achievement compared with current clinical practice. Although this study is promising, prospective validation of this or similar cystatin C-inclusive dosing models is warranted.     

Pharmacokinetics of Posaconazole Suspension in Lung Transplant Patients with and without Cystic Fibrosis

Invasive fungal infections (IFIs) are common among lung transplant recipients (LTRs). Posaconazole is an important antifungal agent for both prophylaxis and treatment of IFIs; however, detailed pharmacokinetic data are limited among LTRs, particularly those with cystic fibrosis (CF). Our objective was to conduct a pharmacokinetic study of posaconazole oral suspension among LTRs, with particular attention to patients with CF. We enrolled 20 LTRs, 7 with CF and 13 with other underlying lung diseases. Average daily doses in CF and non-CF patients were 829 and 862 mg, respectively. After ≥5 days of treatment, only 4 patients had average plasma concentrations of >0.7 μg/ml. Average steady-state plasma concentrations were 61% lower in CF patients (0.233 μg/ml) than in non-CF LTRs (0.594 μg/ml; P = 0.03). The average dose-normalized plasma area-under-the-curve (AUC) values were also lower in CF (0.007 h·μg/ml) than in non-CF LTRs (0.02 h·μg/ml; P = 0.02). The weight-normalized apparent oral clearance values were 2.51 and 0.74 liters/h/kg among CF and non-CF LTRs, respectively (P = 0.005). Despite significant interpatient variability, plasma trough concentrations were strongly correlated with posaconazole AUC across all LTRs (r² = 0.95, P < 0.0001). Taken together, our study highlights a critical need to incorporate new formulations of posaconazole into prophylaxis and treatment strategies for LTRs, particularly those with CF. Future pharmacokinetic studies of both tablet and intravenous formulations must consider LTR-specific factors and incorporate a therapeutic drug monitoring plan in this patient population.