The randomized controlled trial (NAVKIDS2) of a patient navigator program created for children with chronic kidney disease.

Patient navigators enable adult patients to circumnavigate complex health systems, improving access to health care and outcomes. Here, we aimed to evaluate the effects of a patient navigation program in children with chronic kidney disease (CKD). In this multi-center, randomized controlled trial, we randomly assigned children (aged 0-16 years) with CKD stages 1-5 (including children on dialysis or with kidney transplants), from low socioeconomic status backgrounds, and/or residing in remote areas, to receive patient navigation at randomization (immediate) or at six months (waitlist). The primary outcome was self-rated health (SRH) of participating children at six months, using intention to treat analysis. Secondary outcomes included caregivers' SRH and satisfaction with health care, children's quality of life, hospitalizations, and missed school days. Repeated measures of the primary outcome from baseline to six months were analyzed using cumulative logit mixed effects models. Semi-structured interviews were thematically evaluated. Of 398 screened children, 162 were randomized (80 immediate and 82 waitlist); mean age (standard deviation) of 8.8 (4.8) years with 64.8% male. SRH was not significantly different between the immediate and wait-listed groups at six months. There were also no differences across all secondary outcomes between the two groups. Caregivers' perspectives were reflected in seven themes: easing mental strain, facilitating care coordination, strengthening capacity to provide care, reinforcing care collaborations, alleviating family tensions, inability to build rapport and unnecessary support. Thus, in children with CKD, self-rated health may not improve in response to a navigator program, but caregivers gained skills related to providing and accessing care.

Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial.

BACKGROUND: Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. METHODS: BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). FINDINGS: Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48). INTERPRETATION: Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. FUNDING: Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.

Baseline characteristics of participants in the NAVKIDS2 trial: a patient navigator program in children with chronic kidney disease.

BACKGROUND: Children with chronic kidney disease (CKD) require multidisciplinary care to meet their complex healthcare needs. Patient navigators are trained non-medical personnel who assist patients and caregivers to overcome barriers to accessing health services through care coordination. This trial aims to determine the effectiveness of a patient navigator program in children with CKD. METHODS: The NAVKIDS2 trial is a multi-center, waitlisted, randomized controlled trial of patient navigators in children with CKD conducted at five sites across Australia. Children (0-16 years) with CKD from low socioeconomic status rural or remote areas were randomized to an intervention group or a waitlisted control group (to receive intervention after 6 months). The study primary and secondary endpoints include the self-rated health (SRH) (primary), and utility-based quality of life, progression of kidney dysfunction of the child, SRH, and satisfaction with healthcare of the caregiver at 6 months post-randomization. RESULTS: The trial completed recruitment in October 2021 with expected completion of follow-up by October 2022. There were 162 patients enrolled with 80 and 82 patients randomized to the immediate intervention and waitlisted groups, respectively. Fifty-eight (36%) participants were from regional/remote areas, with a median (IQR) age of 9.5 (5.0, 13.0) years, 46% were of European Australian ethnicity, and 65% were male. A total of 109 children (67%) had CKD stages 1-5, 42 (26%) were transplant recipients, and 11 (7%) were receiving dialysis. CONCLUSION: The NAVKIDS2 trial is designed to evaluate the effectiveness of patient navigation in children with CKD from families experiencing socioeconomic disadvantage. A higher resolution version of the Graphical abstract is available as Supplementary information.

Population Pharmacokinetics of Intraperitoneal Gentamicin and the Impact of Varying Dwell Times on Pharmacodynamic Target Attainment in Patients with Acute Peritonitis Undergoing Peritoneal Dialysis.

While the use of intraperitoneal (i.p.) gentamicin is common in the treatment of peritoneal dialysis (PD)-related infections, the ability of these regimens to attain pharmacodynamic target indices of interest in blood and dialysate has not been widely reported. Pharmacokinetic (PK) data were obtained and analyzed from a multiple-dose PK study of i.p. gentamicin with 24 patients who received the drug at 0.6 mg/kg dose of body weight. The probability of target attainment (PTA) for indices of treatment success (i.p. peak/MIC ratio > 10) and toxicity (plasma area under the concentration-time curve [AUC] < 120 mg·h/L) was determined for 0.3- to 1.2-mg/kg i.p. regimens every 24 h for dwell times of 2 to 6 h and for the duration of a 2-week course. In the peritoneum, successful PTA was achieved by all of the simulated regimens up to an MIC of 1 mg/L and by doses equal to or greater than 0.6 mg/kg up to the MIC of 2 mg/L. At the susceptibility breakpoint of 4 mg/L, only the highest dose of 1.2 mg/kg is likely to provide adequate PTA. The probability of achieving exposure below the threshold of 120 mg·h/L in the daily AUC in plasma seems acceptable for all regimens at or below 0.6 mg/kg. Based on the model we developed, a gentamicin dose of 0.6 mg/kg is sufficient to treat organisms with an MIC of ≤2 mg/L without the risk of significant systemic exposure. The 1.2-mg/kg dose necessary to reach the pharmacodynamic target for efficacy at the clinical breakpoint of 4 mg/L is likely to produce early toxic levels of exposure that are expected to be detrimental to the renal system.

Microbiological contamination of indoor and outdoor environments in a desert climate.

Microbiological air contamination in the desert environment is becoming an essential subject for the health of office building occupants and public health. In this study, the concentrations and compositions of airborne microorganisms (bacteria and fungi) were assessed in indoor and outdoor environments using a multistory building complex in Kuwait as a case study. Airborne microorganism samples were collected from 12 sites within the building complex containing nineteen stories over four seasons. Culturable airborne bacteria and fungi were impacted on selected media to determine their concentrations and compositions with a Biolog Omnilog GEN III system and Biolog MicroStation. The indoor mean airborne bacterial count concentrations ranged from 35 to 18,463 CFU/m3, concentrations that are higher than 2,000 CFU/m3, demonstrating high-very high contamination levels in all seasons. Fungal contamination was high in winter and summer, with detected concentrations > 2,000 CFU/m3. Indoor-to-outdoor (I/O) ratios showed that airborne microbial contamination inside building floors originated from indoor air contamination. All the building floors showed bacterial and fungal concentrations ranging from less than 2,000 to more than 2,000 CFU/m3, indicative of a high to very high air contamination level. Statistical analysis showed no correlation between bacterial and fungal concentrations, demonstrating that they originated from unrelated sources. In the indoor building air, the most prevalent bacterial isolate was Bacillus pseudomycoides/cereus, whereas the most dominant fungal isolate was Aspergillus spp. The low count for indoor air bacterial species suggested no particular health risk for the occupants. In contrast, the high count of indoor air fungal species in the winter samples and the presence of potentially allergenic genera detected may suggest possible health risks for the occupants. The results obtained are the basis for the recommendation that the maintenance activities of the HVAC system and the periodical cleaning operation program be revised and preplanned as protective measures.

Are interstitial fluid concentrations of meropenem equivalent to plasma concentrations in critically ill patients receiving continuous renal replacement therapy?

OBJECTIVES: To describe the interstitial fluid (ISF) and plasma pharmacokinetics of meropenem in patients on continuous venovenous haemodiafiltration (CVVHDF). PATIENTS AND METHODS: This was a prospective observational pharmacokinetic study. Meropenem (500 mg) was administered every 8 h. CVVHDF was targeted as a 2-3 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2 and a blood flow rate of 200 mL/min. Serial blood (pre- and post-filter), filtrate/dialysate and ISF concentrations were measured on 2 days of treatment (Profiles A and B). Subcutaneous tissue ISF concentrations were determined using microdialysis. RESULTS: A total of 384 samples were collected. During Profile A, the comparative median (IQR) ISF and plasma peak concentrations were 13.6 (12.0-16.8) and 40.7 (36.6-45.6) mg/L and the trough concentrations were 2.6 (2.4-3.4) and 4.9 (3.5-5.0) mg/L, respectively. During Profile B, the ISF trough concentrations increased by ∼40%. Meropenem ISF penetration was estimated at 63% (60%-69%) and 69% (65%-74%) for Profiles A and B, respectively, using comparative plasma and ISF AUCs. For Profile A, the plasma elimination t1/2 was 3.7 (3.3-4.0) h, the volume of distribution was 0.35 (0.25-0.46) L/kg, the total clearance was 4.1 (4.1-4.8) L/h and the CVVHDF clearance was 2.9 (2.7-3.1) L/h. CONCLUSIONS: This is the first known report of concurrent plasma and ISF concentrations of a meropenem antibiotic during CVVHDF. We observed that the ISF concentrations of meropenem were significantly lower than the plasma concentrations, although the present dose was appropriate for infections caused by intermediately susceptible pathogens (MIC≤4 mg/L).

Microbiological Indoor and Outdoor Air Quality in Chicken Fattening Houses.

This study was conducted at one of the largest poultry companies in Kuwait during November and December 2019 to evaluate the microbiological threats of Escherichia coli (APEC), Salmonella spp., and Aspergillus fumigatus to chickens in fattening houses by counting and identifying the microorganisms by culturing and pyrosequencing analysis. During the fattening cycle, the temperature and humidity ranged between 23.6°C and 29°C and 64.1% and 87.1%, respectively. The total bacterial population and Aspergillus fumigatus measured in the indoor and outdoor air exhibited a linear relationship during the fattening cycle. The total bacterial and Aspergillus concentrations determined during the cycle ranged between 150 and 2000 CFU/m3 and 0 and 1000 CFU/m3, respectively. E. coli and Salmonella spp. concentrations determined during the cycle ranged between 1 and 220 CFU/m3 and 4 and 110 CFU/m3, respectively. Pyrosequencing analysis of the air inside the houses at the end of the cycle revealed extensive biodiversity in the microorganisms, detecting 32 bacterial genera and 14 species. The identified species belonging to the genera Corynebacterium, Haemophilus, Streptococcus, Veillonella, and Aspergillus were identified as potentially affecting human and broiler health. The emission of potentially pathogenic bacteria to the outdoor environment from chicken housing can pose a considerable risk to human health and environmental microbial pollution. This study could guide the development of integrated control devices for monitoring microbes in broiler production facilities during chicken collection for transport to slaughterhouses.

NAVKIDS2 trial: a multi-centre, waitlisted randomised controlled trial of a patient navigator intervention in children with chronic kidney disease - statistical analysis plan and update to the protocol.

BACKGROUND: This update summarises key changes made to the protocol since the publication of the original protocol for the NAVKIDS2 trial of patient navigators for children with chronic kidney disease (CKD) experiencing social disadvantage and provides the statistical analysis plan (SAP) which has not previously been published. METHODS/DESIGN: The original protocol was published in BMC Nephrology ( https://doi.org/10.1186/s12882-019-1325-y ) prior to the commencement of trial recruitment. During the course of the trial, some key methodological changes needed to be made including changes to eligibility criteria (addition of patients with CKD stages 1-2, broadening of financial status eligibility criterion, addition of patients living in rural/remote areas, modification of age eligibility to 0-16 years, addition of limits related to the language spoken by family, guidance regarding families with multiple eligible children), changes to sites, reduction of sample size, addition of virtual options for consent and study procedures in response to the COVID-19 pandemic, removal of staggered recruitment across sites, addition of outcomes, and changes to the timing and number of assessments. This update summarises the changes made and their rationale and provides the detailed plan for statistical analysis of the trial. These changes have been finalised prior to the completion of study follow-up and the commencement of data analysis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618001152213 . Prospectively registered on 12 July 2018.

Baseline Characteristics and Representativeness of Participants in the BEST-Fluids Trial: A Randomized Trial of Balanced Crystalloid Solution Versus Saline in Deceased Donor Kidney Transplantation.

Delayed graft function (DGF) is a major complication of deceased donor kidney transplantation. Saline (0.9% sodium chloride) is a commonly used intravenous fluid in transplantation but may increase the risk of DGF because of its high chloride content. Better Evidence for Selecting Transplant Fluids (BEST-Fluids), a pragmatic, registry-based, double-blind, randomized trial, sought to determine whether using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce DGF. We sought to evaluate the generalizability of the trial cohort by reporting the baseline characteristics and representativeness of the trial participants in detail. Methods: We compared the characteristics of BEST-Fluids participants with those of a contemporary cohort of deceased donor kidney transplant recipients in Australia and New Zealand using data from the Australia and New Zealand Dialysis and Transplant Registry. To explore potential international differences, we compared trial participants with a cohort of transplant recipients in the United States using data from the Scientific Registry of Transplant Recipients. Results: During the trial recruitment period, 2373 deceased donor kidney transplants were performed in Australia and New Zealand; 2178 were eligible' and 808 were enrolled in BEST-Fluids. Overall, trial participants and nonparticipants were similar at baseline. Trial participants had more coronary artery disease (standardized difference [d] = 0.09; P = 0.03), longer dialysis duration (d = 0.18, P < 0.001), and fewer hypertensive (d = -0.11, P = 0.03) and circulatory death (d = -0.14, P < 0.01) donors than nonparticipants. Most key characteristics were similar between trial participants and US recipients, with moderate differences (|d| ≥ 0.2; all P < 0.001) in kidney failure cause, diabetes, dialysis duration, ischemic time, and several donor risk predictors, likely reflecting underlying population differences. Conclusions: BEST-Fluids participants had more comorbidities and received slightly fewer high-risk deceased donor kidneys but were otherwise representative of Australian and New Zealand transplant recipients and were generally similar to US recipients. The trial results should be broadly applicable to deceased donor kidney transplantation practice worldwide.

Conducting clinical trials during the COVID-19 pandemic-a collaborative trial network response.

The unprecedented demand placed on healthcare systems from the COVID-19 pandemic has forced a reassessment of clinical trial conduct and feasibility. Consequently, the Australasian Kidney Trials Network (AKTN), an established collaborative research group known for conducting investigator-initiated global clinical trials, had to efficiently respond and adapt to the changing landscape during COVID-19. Key priorities included ensuring patient and staff safety, trial integrity and network sustainability for the kidney care community. New resources have been developed to enable a structured review and contingency plan of trial activities during the pandemic and beyond.

Pharmacokinetics and pharmacodynamics in critically ill patients.

PURPOSE OF REVIEW: The purpose of this review is to highlight the recently published studies in the area of pharmacokinetics and pharmacodynamics in critically ill patients and ascertain the relevance to clinical practice. RECENT FINDINGS: The majority of the published studies in this area were related to antibiotics and this will form the main focus of this review. A number of studies have focused on antibiotic concentrations at various target sites of infection or other tissue sites including cerebrospinal fluid, peritoneal fluid and burns tissues. The administration of time-dependent antibiotics using continuous infusion has also been the subject of recently published studies which support the superior achievement of pharmacodynamic targets using continuous infusion compared with bolus dosing. Antibiotic dosing during renal replacement therapies, mainly during extended daily dialysis (EDD) and during other forms of extracorporeal techniques including extracorporeal membrane oxygenation (ECMO), have also been described in a few recent studies and case reports. SUMMARY: Studies have shown that critically ill patients display large variations in pharmacokinetics mainly due to altered pathophysiology. An understanding of the pathophysiological changes that occur in critically ill patients is essential to optimize dosing particularly to achieve the pharmacodynamic targets for antibiotics.

Study Protocol for Better Evidence for Selecting Transplant Fluids (BEST-Fluids): a pragmatic, registry-based, multi-center, double-blind, randomized controlled trial evaluating the effect of intravenous fluid therapy with Plasma-Lyte 148 versus 0.9% saline on delayed graft function in deceased donor kidney transplantation.

BACKGROUND: Delayed graft function, the requirement for dialysis due to poor kidney function post-transplant, is a frequent complication of deceased donor kidney transplantation and is associated with inferior outcomes and higher costs. Intravenous fluids given during and after transplantation may affect the risk of poor kidney function after transplant. The most commonly used fluid, isotonic sodium chloride (0.9% saline), contains a high chloride concentration, which may be associated with acute kidney injury, and could increase the risk of delayed graft function. Whether using a balanced, low-chloride fluid instead of 0.9% saline is safe and improves kidney function after deceased donor kidney transplantation is unknown. METHODS: BEST-Fluids is an investigator-initiated, pragmatic, registry-based, multi-center, double-blind, randomized controlled trial. The primary objective is to compare the effect of intravenous Plasma-Lyte 148 (Plasmalyte), a balanced, low-chloride solution, with the effect of 0.9% saline on the incidence of delayed graft function in deceased donor kidney transplant recipients. From January 2018 onwards, 800 participants admitted for deceased donor kidney transplantation will be recruited over 3 years in Australia and New Zealand. Participants are randomized 1:1 to either intravenous Plasmalyte or 0.9% saline peri-operatively and until 48 h post-transplant, or until fluid is no longer required; whichever comes first. Follow up is for 1 year. The primary outcome is the incidence of delayed graft function, defined as dialysis in the first 7 days post-transplant. Secondary outcomes include early kidney transplant function (composite of dialysis duration and rate of improvement in graft function when dialysis is not required), hyperkalemia, mortality, graft survival, graft function, quality of life, healthcare resource use, and cost-effectiveness. Participants are enrolled, randomized, and followed up using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. DISCUSSION: If using Plasmalyte instead of 0.9% saline is effective at reducing delayed graft function and improves other clinical outcomes in deceased donor kidney transplantation, this simple, inexpensive change to using a balanced low-chloride intravenous fluid at the time of transplantation could be easily implemented in the vast majority of transplant settings worldwide. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12617000358347. Registered on 8 March 2017. ClinicalTrials.gov: NCT03829488. Registered on 4 February 2019.

Optimising intraperitoneal gentamicin dosing in peritoneal dialysis patients with peritonitis (GIPD) study.

BACKGROUND: Antibiotics are preferentially delivered via the peritoneal route to treat peritonitis, a major complication of peritoneal dialysis (PD), so that maximal concentrations are delivered at the site of infection. However, drugs administered intraperitoneally can be absorbed into the systemic circulation. Drugs excreted by the kidneys accumulate in PD patients, increasing the risk of toxicity. The aim of this study is to examine a model of gentamicin pharmacokinetics and to develop an intraperitoneal drug dosing regime that maximises bacterial killing and minimises toxicity. METHODS/DESIGN: This is an observational pharmacokinetic study of consecutive PD patients presenting to the Royal Brisbane and Women's Hospital with PD peritonitis and who meet the inclusion criteria. Participants will be allocated to either group 1, if anuric as defined by urine output less than 100 ml/day, or group 2: if non-anuric, as defined by urine output more than 100 ml/day. Recruitment will be limited to 15 participants in each group. Gentamicin dosing will be based on the present Royal Brisbane & Women's Hospital guidelines, which reflect the current International Society for Peritoneal Dialysis Peritonitis Treatment Recommendations. The primary endpoint is to describe the pharmacokinetics of gentamicin administered intraperitoneally in PD patients with peritonitis based on serial blood and dialysate drug levels. DISCUSSION: The study will develop improved dosing recommendations for intraperitoneally administered gentamicin in PD patients with peritonitis. This will guide clinicians and pharmacists in selecting the most appropriate dosing regime of intraperitoneal gentamicin to treat peritonitis. TRIAL REGISTRATION: ACTRN12609000446268.

Persistent organic pollutants in infants and toddlers: Relationship between concentrations in matched plasma and faecal samples.

Early-childhood biomonitoring of persistent organic pollutants (POPs) is challenging due to the logistic and ethical limitations associated with blood sampling. We investigated using faeces as a non-invasive matrix to estimate internal exposure to POPs. The concentrations of selected POPs were measured in matched plasma and faecal samples collected from 20 infants/toddlers (aged 13±4.8months), including a repeat sample time point for 13 infants (~5months apart). We observed higher rates of POP quantification in faeces (2g dry weight) than in plasma (0.5mL). Among the five chemicals that had quantification frequencies over 50% in both matrices, except for HCB, log concentration in faeces (Cf) and blood (Cb) were correlated (r>0.74, P<0.05) for p.p'-dichlorodiphenyldichloroethylene (p,p'-DDE), 2,3',4,4',5-pentachlorobiphenyl (PCB118), 2,2',3,4,4',5'-pentachlorobiphenyl (PCB138) and 2,2',4,4',5,5'-pentachlorobiphenyl (PCB153). We determined faeces:plasma concentration ratios (Kfb), which can be used to estimate Cb from measurements of Cf for infants/toddlers. For a given chemical, the variation in Kfb across individuals was considerable (CV from 0.46 to 0.70). Between 5% and 50% of this variation was attributed to short-term intra-individual variability between successive faecal samples. This variability could be reduced by pooling faeces samples over several days. Some of the remaining variability was attributed to longer-term intra-individual variability, which was consistent with previously reported observations of a decrease in Kfb over the first year of life. The strong correlations between Cf and Cb demonstrate the promise of using faeces for biomonitoring of these compounds. Future research on the sources of variability in Kfb could improve the precision and utility of this technique.

Pharmacokinetics of Intraperitoneal Cefalothin and Cefazolin in Patients Being Treated for Peritoneal Dialysis-Associated Peritonitis.

UNLABELLED: ♦ BACKGROUND: The standard treatment of peritoneal dialysis (PD)-associated peritonitis (PD-peritonitis) is intraperitoneal (IP) administration of antibiotics. Only limited data on the pharmacokinetics and appropriateness of contemporary dose recommendations of IP cefalothin and cefazolin exist. The aim of this study was to describe the pharmacokinetics of IP cefalothin and cefazolin in patients treated for PD-peritonitis. ♦ METHODS: As per international guidelines, IP cefalothin or cefazolin 15 mg/kg once daily was dosed with gentamicin in a 6-hour dwell to patients with PD-peritonitis during routine care. Serial plasma and PD effluent samples were collected over the first 24 hours of therapy. Antibiotic concentrations were quantified using a validated chromatographic method with pharmacokinetic analysis performed using a non-compartmental approach. ♦ RESULTS: Nineteen patients were included (cefalothin n = 8, cefazolin n = 11). The median bioavailability for both antibiotics exceeded 92%, but other pharmacokinetic parameters varied markedly between antibiotics. Both antibiotics achieved high PD effluent concentrations throughout the antibiotic dwell. Cefazolin had a smaller volume of distribution compared with cefalothin (14 vs 40 L, p = 0.003). The median trough total plasma antibiotic concentration for cefazolin and cefalothin during the dwell differed (plasma 56 vs 13 mg/L, p < 0.0001) despite a similar concentration in PD effluent (37 vs 38 mg/L, p = 0.58). Lower antibiotic concentrations were noted during PD dwells not containing antibiotic, particularly cefalothin, which was frequently undetectable in plasma and PD effluent. The median duration that the unbound antibiotic concentration was above the minimum inhibitory concentration (MIC) was approximately 13% (plasma) and 25% (IP) for cefalothin, and 100% (plasma and IP) for cefazolin, of the dosing interval. ♦ CONCLUSIONS: When IP cefalothin or cefazolin is allowed to dwell for 6 hours, sufficient PD effluent concentrations are present for common pathogens during this time. However, with once-daily IP dosing, in contrast to cefazolin, there is a risk of subtherapeutic plasma and PD effluent cefalothin concentrations, so more frequent dosing may be required.

Pharmacokinetics of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration.

This prospective pharmacokinetic study aimed to describe plasma and interstitial fluid (ISF) pharmacokinetics of piperacillin and tazobactam in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF). Piperacillin/tazobactam (4g/0.5g) was administered every 8h and CVVHDF was performed as a 3-3.5L/h exchange using a polyacrylonitrile filter with a surface area of 1.05m(2). Serial blood (pre- and post-filter), filtrate/dialysate, urine and ISF concentrations were measured. Subcutaneous tissue ISF concentrations were determined using microdialysis. A total of 407 samples were collected. Median peak plasma concentrations were 210.5 (interquartile range=161.5-229.0) and 29.4 (27.9-32.0) mg/L and median trough plasma concentrations were 64.3 (49.0-68.9) and 12.3 (7.7-13.7) mg/L for piperacillin and tazobactam, respectively. The plasma elimination half-life was 6.4 (4.6-8.7) and 7.3 (4.6-11.8) h, volume of distribution 0.42 (0.29-0.49) and 0.32 (0.24-0.36) L/kg, total clearance 5.1 (4.2-6.2) and 3.8 (3.3-4.2) L/h and CVVHDF clearance 2.5 (2.3-3.1) and 2.5 (2.3-3.2) L/h for piperacillin and tazobactam, respectively. The tissue penetration ratio or ratio of area under the concentration-time curve of the unbound drug in ISF to plasma (unbound AUCISF/AUCplasma) was ca. 1 for both piperacillin and tazobactam. This is the first report of concurrent plasma and ISF concentrations of piperacillin and tazobactam during CVVHDF. For the CVVHDF settings used in this study, a dose of 4.5g piperacillin/tazobactam administered evry 8h resulted in piperacillin concentrations in plasma and ISF >32mg/L throughout most of the dosing interval.

Subtherapeutic initial ß-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations.

BACKGROUND: ß-Lactams are routinely used as empirical therapy in critical illness, with extended concentrations above the minimum inhibitory concentration (MIC) of the infecting organism required for effective treatment. Changes in renal function in this setting can significantly impact the probability of achieving such targets. METHODS: Analysis was made of trough plasma drug concentrations obtained via therapeutic drug monitoring, compared with renal function, in critically ill patients receiving empirical ß-lactam therapy. Drug concentrations were measured by means of high-performance liquid chromatography and corrected for protein binding. Therapeutic levels were defined as greater than or equal to MIC and greater than or equal to four times MIC (maximum bacterial eradication), respectively. Renal function was assessed by means of an 8-h creatinine clearance (CLCR). RESULTS: Fifty-two concurrent trough concentrations and CLCR measures were used in analysis. Piperacillin was the most frequent ß-lactam prescribed (48%), whereas empirical cover and Staphylococcus species were the most common indications for therapy (62%). Most patients were mechanically ventilated on the day of study (85%), although only 25% were receiving vasopressors. In only 58% (n = 30) was the trough drug concentration greater than or equal to MIC, falling to 31% (n = 16) when using four times MIC as the target. CLCR values ≥ 130 mL/min/1.73 m2 were associated with trough concentrations less than MIC in 82% (P < .001) and less than four times MIC in 72% (P < .001). CLCR remained a significant predictor of subtherapeutic concentrations in multivariate analysis. CONCLUSION: Elevated CLCR appears to be an important predictor of subtherapeutic ß-lactam concentrations and suggests an important role in identifying such patients in the ICU.

Pharmacokinetics of intraperitoneal gentamicin in peritoneal dialysis patients with peritonitis (GIPD study).

BACKGROUND AND OBJECTIVES: Peritonitis is a major infectious complication in peritoneal dialysis patients, and intraperitoneal antibiotic administration is preferred to ensure maximal antibiotic concentrations at the site of infection. This study aimed to describe the plasma and infection site pharmacokinetics of intraperitoneal gentamicin in patients with peritonitis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This prospective pharmacokinetic study of intraperitoneal gentamicin was conducted in peritoneal dialysis patients presenting to hospital with clinically defined signs and symptoms of peritonitis. Twenty-four patients were administered a 0.6-mg/kg dose of intraperitoneal gentamicin, which was allowed to dwell for 6 hours. Serial blood and dialysate samples were collected for 24 hours after the first dose. Gentamicin concentrations in plasma and dialysate were measured using a validated assay. RESULTS: The median percentage of the dose absorbed into the systemic circulation was 76% (interquartile range=69%-82%) and significantly different between patients with low average, high average, and high peritoneal membrane transporter status (P=0.03). The calculated pharmacokinetic parameters were plasma terminal elimination half-life of 24.7 (20.4-29.9) hours, terminal volume of distribution of 0.30 (0.20-0.36) L/kg, observed peak plasma concentration of 3.1 (2.4-3.4) mg/L, and observed trough plasma concentration of 1.9 (1.4-2.2) mg/L. The peak gentamicin concentration in dialysate was at least eight times the minimum inhibitory concentration of the likely pathogens. CONCLUSIONS: The high systemic absorption of gentamicin in patients with peritonitis and prolonged plasma elimination half-life may lead to drug accumulation in the systemic circulation, increasing the risk of toxicity.

Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock.

Antimicrobial pharmacokinetics (PK) and pharmacodynamics (PD) are important considerations, particularly in critically ill patients with severe sepsis and septic shock. The pathophysiologic changes that occur in these conditions can have a major effect on pharmacokinetic parameters, which in turn could result in failure to achieve pharmacodynamic targets for antimicrobials thus adversely affecting clinical outcome. This paper discusses the pathophysiologic changes that occur during severe sepsis and septic shock and the consequent effects on antimicrobial PK and PD. The effect of PK/PD on specific antimicrobial classes is discussed and a rational framework for antimicrobial dosing is provided. Knowledge of PK/PD properties of antimicrobials can be used to personalize dosing regimens not only to maximize antimicrobial activity but also to minimize toxicity and reduce the development of antimicrobial resistance.