Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy

ABSTRACT Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae . Current dosing regimens recommend the administration of 0.25 to 0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g posthemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem. Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode. The mean hemofilter clearance was 123.46 ± 42.03 ml/min, and the total body clearance between hemodialysis sessions was 16.79 ± 6.02 ml/min. The average prehemodialysis trough concentration was 2.4 ± 1.3 mg/liter, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/liter. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients. Our data indicate that posthemodialysis administration of 1 g of doripenem results in sufficient plasma levels in anuric but not oliguric patients during the entire dosing interval. (This trial was registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.)

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Pharmacokinetics of Benzylpenicillin (Penicillin G) during Prolonged Intermittent Renal Replacement Therapy

Chemotherapy ◽

10.1159/000499375 ◽

2019 ◽

Vol 64 (1) ◽

pp. 17-21 ◽

Cited By ~ 2

Author(s):

Vesa Cheng ◽

Matthew Rawlins ◽

Tim Chang ◽

Emma Fox ◽

John Dyer ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Renal Replacement Therapy ◽

Replacement Therapy ◽

Critically Ill ◽

Critically Ill Patients ◽

Penicillin G ◽

Blood Samples ◽

Staphylococcus Aureus Bacteremia ◽

The Mean ◽

Intermittent Renal Replacement Therapy

Prolonged intermittent renal replacement therapy (PIRRT) is an increasingly adopted method of renal replacement in critically ill patients. Like continuous renal replacement therapy, PIRRT can alter the pharmacokinetics (PK) of many drugs. In this setting, dosing data for antibiotics like benzylpenicillin are lacking. In order to enable clinicians to prescribe benzylpenicillin safely and effectively, knowledge of the effects of PIRRT on the plasma PK of benzylpenicillin is required. Herein, we describe the PK of benzylpenicillin in 2 critically ill patients on PIRRT for the treatment of penicillin-susceptible Staphylococcus aureus bacteremia complicated by infective endocarditis. Blood samples were taken for each patient taken over dosing periods during PIRRT and off PIRRT. Two-compartment PK models described significant differences in the mean clearance of benzylpenicillin with and without PIRRT (6.61 vs. 3.04 L/h respectively). We would suggest a benzylpenicillin dose of 1,800 mg (3 million units) every 6-h during PIRRT therapy as sufficient to attain PK/pharmacodynamic target.

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Ex VivoCharacterization of Effects of Renal Replacement Therapy Modalities and Settings on Pharmacokinetics of Meropenem and Vaborbactam

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01306-18 ◽

2018 ◽

Vol 62 (10) ◽

Cited By ~ 8

Author(s):

Fekade B. Sime ◽

Saurabh Pandey ◽

Nermin Karamujic ◽

Suzanne Parker ◽

Elizabeth Alexander ◽

...

Keyword(s):

Renal Replacement Therapy ◽

Replacement Therapy ◽

Surface Area ◽

Flow Rate ◽

Ex Vivo ◽

Flow Rates ◽

Content Type ◽

Carbapenem Resistant ◽

Effluent Flow Rate ◽

The Mean

ABSTRACTThe combination product meropenem-vaborbactam, with activity against KPC-producing carbapenem-resistantEnterobacteriaceae, is likely to be used during renal replacement therapy. The aim of this work was to describe the extracorporeal removal (adsorption and clearance) of meropenem-vaborbactam during continuous venovenous hemofiltration (CVVH). Anex vivomodel was used to examine the effects of a matrix of operational settings. Vaborbactam did not adsorb to AN69 (acrylonitrile and sodium methallylsulfonate copolymer) ST100 (surface area, 1 m2) hemofilter; the mean (±standard deviation [SD]) meropenem adsorption was 9% (±1%). The sieving coefficients (mean ± SD) with AN69 ST100 and ST150 (surface area, 1.5 m2) filters ranged from 0.97 ± 0.16 to 1.14 ± 0.12 and from 1.13 ± 0.01 to 1.53 ± 0.28, respectively, for meropenem and from 0.64 ± 0.39 to 0.90 ± 0.14 and 0.78 ± 0.18 to 1.04 ± 0.28, respectively, for vaborbactam. At identical settings, vaborbactam sieving coefficients were 25% to 30% lower than for meropenem. Points of dilution, blood flow rates, or effluent flow rates did not affect sieving coefficients for either drug. However, doubling the effluent flow rate resulted in >50 to 100% increases in filter clearance for both drugs. Postfilter dilution resulted in 40 to 80% increases in filter clearance at a high effluent flow rate (4,000 ml/h), compared with ∼15% increases at a low effluent flow rate (1,000 ml/h) for both drugs. For all combinations of setting and filters tested, vaborbactam clearance was lower than that of meropenem by ∼20 to 40%. Overall, meropenem-vaborbactam is efficiently cleared in CVVH mode.

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Doripenem Treatment during Continuous Renal Replacement Therapy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01801-15 ◽

2015 ◽

Vol 60 (3) ◽

pp. 1687-1694 ◽

Cited By ~ 7

Author(s):

M. G. Vossen ◽

J. M. Wenisch ◽

A. Maier-Salamon ◽

A. Fritsch ◽

K. Saria ◽

...

Keyword(s):

Renal Replacement Therapy ◽

Continuous Renal Replacement Therapy ◽

Replacement Therapy ◽

Care Setting ◽

Volume Of Distribution ◽

Intensive Care Setting ◽

Dosing Regimen ◽

Content Type ◽

The Mean ◽

Trough Levels

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity againstPseudomonas aeruginosa. While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based on nonseptic patients, while newer publications chose comparatively low target concentrations for a carbapenem. Thus, there is an urgent need for updated recommendations for dosing during cRRT. In the trial presented here, we included 13 oliguric septic patients undergoing cRRT in an intensive care setting. Five patients each were treated with hemodiafiltration or hemodialysis, while three patients received hemofiltration treatment. All patients received 1 g doripenem every 8 h. Doripenem concentrations in the plasma and ultrafiltrate were measured over 48 h. The mean hemofilter clearance was 36.53 ml/min, and the mean volume of distribution was 59.26 liters. The steady-state trough levels were found at 8.5 mg/liter, with no considerable accumulation. Based on pharmacokinetic and pharmacodynamic considerations, we propose a regimen of 1 g q8h, which may be combined with a loading dose of 1.5 to 2 g for critically ill patients. (This study has been registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.)

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POS0119 RENAL INVOLVEMENT AND NEED OF RENAL REPLACEMENT THERAPY IN ANCA ASSOCIATED VASCULITIS IN A SPANISH SINGLE-CENTER STUDY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.345 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 270.2-271

Author(s):

J. Álvarez Troncoso ◽

J. C. Santacruz Mancheno ◽

A. Díez Vidal ◽

S. Afonso Ramos ◽

A. Noblejas Mozo ◽

...

Keyword(s):

Renal Replacement Therapy ◽

Replacement Therapy ◽

Granulomatosis With Polyangiitis ◽

Renal Involvement ◽

Age At Diagnosis ◽

Systemic Involvement ◽

Risk Of Death ◽

Anca Associated Vasculitis ◽

The Mean

Background:Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EPGA). Renal involvement is frequent in AAV and is an important factor for morbidity and mortality.Objectives:The main objective of this study was to analyze the demographic, clinical, histological and therapeutic characteristics of renal involvement in patients with AAV and the risk of renal replacement therapy (RRT) or death.Methods:Retrospective observational study of 56 patients with AAV fulfilling classificatory criteria and renal involvement diagnosed between 1995 and 2020 from a Spanish tertiary centre. We studied the histological involvement (according to the 2010 classification in focal, crescentic, mixed or sclerotic), immunofluorescence (IF) and the treatment received with the risk of RRT or death.Results:We included 56 patients diagnosed with AAV and renal involvement. The mean age was 61.08±4.05 years; 58.9% were women. The mean follow-up time of these patients was 16.14± 8.80 years. Only 57.1% of patients presented systemic involvement.Most frequent non-renal AAV manifestations were lung involvement (39.3%), central nervous system (30.4%), otorhinolaryngology (ORL) (14.3%), skin (8.9%) and cardiac involvement (8.9%). Main immunological findings were ANCA-MPO+ (69.6%), ANCA-PR3+ (23.2%), ANCA-negative (5.4%). Low C3 was found in 19.6% patients. Histologic classification (HC) and need of RRT is described in table 1. Main HC in renal AAV was crescentic, mixed, focal and sclerotic respectively. Eight patients had not biopsy performed. IF was positive for C3 deposits in 20 patients (35.7%). Half of the patients presented <50% normal glomeruli.The treatment of renal involvement in AAV in our cohort was as follows: 83.9% (47) corticosteroids (CS) and cyclophosphamide (of which 40 received intravenous and 7 oral cyclophosphamide; and 12 patients associated plasma exchange (PE) with this treatment), 5.36% CS alone, 2 patients received CS and mycophenolate; 1 CS and rituximab, 1 CS and PE, and 2 patients received no treatment. A total of 13 patients received PE and 18 RRT. The mean time to RRT was 65.44±32.72 months. Relapses were not uncommon, 33.93% of the patients presented ≥1 relapse and 10.71% presented ≥2.Infections were very frequent since they were present in 91.07% of the patients. Other frequent non-immunological complications observed in the follow-up of these patients were thrombosis in 31.14%, cardiovascular events in 28.57% and cancer in 19.64%.Patients with ANCA-PR3+ were younger at diagnosis (p<0.001), were more likely to present cardiac (p=0.045) and ORL involvement (p<0.001). However, neither ANCA-PR3+ nor ANCA-MPO+ were specifically associated with the need of RRT or higher risk of death in our cohort. Use of CS alone for the treatment of renal AAV was associated with higher mortality (p=0.006) but CS and cyclophosphamide with lower mortality (p=0.044). ANCA-negative patients were more likely to receive no treatment. Having <50% normal glomeruli and C3 deposits on IF were associated with an increased need for RRT. Presenting focal disease on HC was protective for the need of RRT. Older age at diagnosis, systemic involvement of AAV and need of RRT was associated with higher mortality.Conclusion:AAVs are complex vasculitides with frequent renal involvement. Increased C3 deposition, non-focal histological forms, and <50% normal glomeruli were related to the need for RRT. In turn, the need for RRT, a later age at diagnosis, and systemic involvement were associated with higher mortality. Holistic and multidisciplinary early management of AAVs in experience centers can help improve renal prognosis and decrease mortality.References:[1]Binda et al. ANCA-associated vasculitis with renal involvement. J Nephrol. 2018 Apr;31(2):197-208.[2]Kronbichler et al. Clinical associations of renal involvement in ANCA-associated vasculitis. Autoimmun Rev. 2020 Apr;19(4):102495.Disclosure of Interests:None declared

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Intra-dialytic hypotension following the transition from continuous to intermittent renal replacement therapy

Annals of Intensive Care ◽

10.1186/s13613-021-00885-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

William Beaubien-Souligny ◽

Yifan Yang ◽

Karen E. A. Burns ◽

Jan O. Friedrich ◽

Alejandro Meraz-Muñoz ◽

...

Keyword(s):

Renal Replacement Therapy ◽

Hospital Mortality ◽

Replacement Therapy ◽

Kidney Injury ◽

Hemodynamic Instability ◽

Factors Associated ◽

Definition Of ◽

Vasopressor Use ◽

Cumulative Fluid Balance ◽

Intermittent Renal Replacement Therapy

Abstract Background Transition from continuous renal replacement therapy (CRRT) to intermittent renal replacement therapy (IRRT) can be associated with intra-dialytic hypotension (IDH) although data to inform the definition of IDH, its incidence and clinical implications, are lacking. We aimed to describe the incidence and factors associated with IDH during the first IRRT session following transition from CRRT and its association with hospital mortality. This was a retrospective single-center cohort study in patients with acute kidney injury for whom at least one CRRT-to-IRRT transition occurred while in intensive care. We assessed associations between multiple candidate definitions of IDH and hospital mortality. We then evaluated the factors associated with IDH. Results We evaluated 231 CRRT-to-IRRT transitions in 213 critically ill patients with AKI. Hospital mortality was 43.7% (n = 93). We defined IDH during the first IRRT session as 1) discontinuation of IRRT for hemodynamic instability; 2) any initiation or increase in vasopressor/inotropic agents or 3) a nadir systolic blood pressure of < 90 mmHg. IDH during the first IRRT session occurred in 50.2% of CRRT-to-IRRT transitions and was independently associated with hospital mortality (adjusted odds ratio [OR]: 2.71; CI 1.51–4.84, p < 0.001). Clinical variables at the time of CRRT discontinuation associated with IDH included vasopressor use, higher cumulative fluid balance, and lower urine output. Conclusions IDH events during CRRT-to-IRRT transition occurred in nearly half of patients and were independently associated with hospital mortality. We identified several characteristics that anticipate the development of IDH following the initiation of IRRT.

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Pharmacokinetics of Ceftolozane-Tazobactam during Prolonged Intermittent Renal Replacement Therapy

Chemotherapy ◽

10.1159/000493196 ◽

2018 ◽

Vol 63 (4) ◽

pp. 203-206 ◽

Cited By ~ 3

Author(s):

Matthew Rawlins ◽

Vesa Cheng ◽

Edward Raby ◽

John Dyer ◽

Adrian Regli ◽

...

Keyword(s):

Renal Replacement Therapy ◽

Replacement Therapy ◽

Goodness Of Fit ◽

Final Model ◽

Blood Samples ◽

Compartment Models ◽

Log Likelihood ◽

New Antibiotics ◽

Plasma Pharmacokinetics ◽

Intermittent Renal Replacement Therapy

Background: Prolonged intermittent renal replacement therapy (PIRRT) eliminates many drugs, and without dosing data, for new antibiotics like ceftolozane/tazobactam, suboptimal concentrations and treatment failure are likely. Objectives: Herein, we describe the effect of PIRRT on the plasma pharmacokinetics of ceftolozane/tazobactam administered in a critically ill 55-year-old patient with a polymicrobial sternal wound osteomyelitis, including a multiresistant Pseudomonas aeruginosa. Method: Blood samples were taken over 4 days where the patient received a 7.5-h PIRRT treatment. One- and 2-compartment models were tested for ceftolozane and tazobactam separately, and the log-likelihood ratio and goodness-of-fit plots were used to select the final model. Results: Two-compartment models were developed for ceftolozane and tazobactam separately and described significant differences in clearance of ceftolozane and tazobactam with and without PIRRT (8.273 vs. 0.393 and 8.020 vs. 0.767 L/h, respectively). Conclusions: A ceftolozane/tazobactam dose of 500 mg/250 mg appears to be sufficient to attain pharmacokinetic/pharmacodynamic targets during PIRRT while the manufacturer’s recommended dosing of 100 mg/50 mg every 8 h was sufficient during non-PIRRT periods.

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