Tacrolimus (Tac) has a narrow therapeutic window and shows large between-patient pharmacokinetic variability. As a result, over-immunosuppression and under-immunosuppression are frequently ...encountered in daily clinical practice. Unraveling the impact of genetic polymorphisms on Tac pharmacokinetics may help to refine therapy. In this study, the associations of single-nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes (CYP3A) with Tac pharmacokinetics were investigated in renal transplant recipients.
In a cohort of 272 kidney transplant recipients, associations between functional genetic variants (CYP3A4*22 and CYP3A5*3) and dose-adjusted predose Tac concentrations (C0) and daily doses of Tac at days 5-7 and 15 and 1, 3, 6 and 12 months after renal transplantation were evaluated. Patients were genotyped and clustered according to both CYP3A4*22 and CYP3A5*3 allelic status: poor (PM) (CYP3A4*22 carriers with CYP3A5*3/*3), intermediate (IM) (CYP3A4*1/*1 with CYP3A5*3/*3 or CYP3A4*22 carriers with CYP3A5*1 carriers) and extensive CYP3A-metabolizers (EM) (CYP3A4*1/*1 and CYP3A5*1 carriers).
EM had an 88% lower dose-adjusted C0 compared with IM. PM had a 26% higher dose-adjusted C0 compared with IM. The percentage of patients with supratherapeutic Tac exposure (C0>15 ng/ml) was significantly higher in PM (43.5%) compared with EM (0%) at days 5-7 after transplantation (P=0.01). About 30% of EM had subtherapeutic exposure (C0<5 ng/ml) at days 5-7 after transplantation (P=0.001).
The combined CYP3A4 and CYP3A5 genotype of renal transplant recipients has a major influence on the Tac dose required to reach the target exposure.
The administration of β-lactam antibiotics in continuous infusion could let optimize the pharmacokinetic/pharmacodynamic parameters, especially in the treatment of serious bacterial infections. In ...this context, and also due to variability in their plasmatic concentrations, therapeutic drug monitoring (TDM) may be useful to optimize dosing and, therefore, be useful for the clinicians.
We developed and validated a measurement procedure based on ultra-high performance liquid chromatography-tandem mass spectrometry for simultaneous measurement of amoxicillin, ampicillin, cloxacillin, piperacillin, cefepime, ceftazidime, cefuroxime, aztreonam and meropenem concentrations in plasma. The chromatographic separation was achieved using an Acquity®-UPLC® BEH™ (2.1×100mm id, 1.7μm) reverse-phase C18 column, with a water/acetonitrile linear gradient containing 0.1% formic acid at a 0.4mL/min flow rate. β-Lactam antibiotics and their internal standards were detected by electrospray ionization mass spectrometry in multiple reaction monitoring mode.
Chromatography run time was 7.0min and β-lactam antibiotics eluted at retention times ranging between 1.08 and 1.91min. The lower limits of quantification were between 0.50 and 1.00mg/L. Coefficients of variation and relative bias absolute values were <13.3% and 14.7%, respectively. Recovery values ranged from 55.7% to 84.8%. Evaluation of the matrix effect showed ion enhancement for all antibiotics. No interferences or carry-over were observed.
Our measurement procedure could be applied to daily clinical laboratory practice to measure the concentration of β-lactam antibiotics in plasma, for instance in patients with bone and joint infections and critically ill patients.
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•An UPLC-MS/MS procedure for measurement of antibiotic concentrations was developed.•Measurement procedure/system was validated using the EMA validation guideline.•Verification of the applicability of the procedure was performed.•The measurement procedure developed is well suited to routine hospital practice.
Treating patients based on a treat-to-trough approach has been shown to be a cost-effective strategy for inflammatory bowel disease (IBD) patients who have become unresponsive to infliximab (IFX). ...However, the documented evidence for this is limited, and some controversy remains regarding the use of routine proactive therapeutic drug monitoring (TDM). To support routine TDM of IFX and regimen optimization in IBD patients, more in-depth knowledge of the covariates that affect the pharmacokinetic (PK) variability of IFX is needed. The aim of this study was to identify the characteristics of the patient, disease, and treatments that influence IFX PK and exposure in our cohort of IBD patients using a repeated-measures design.
We performed a prospective observational study of adult IBD patients who received IFX between July 2013 and March 2017. We obtained repeated IFX trough concentration (Cmin) measurements and implemented a previously described population pharmacokinetic model to estimate individual clearance (CL). From the individual primary parameters, the area under the curve (AUC), half-life (t1/2), and central elimination rate constant (K10) were estimated. We performed a repeated-measures analysis to evaluate whether patient characteristics, disease status, concomitant immunosuppressive therapy, and immunogenicity are associated with IFX Cmin and PK parameters.
We collected 429 Cmin measurements from 112 patients. The median of the Cmin values was 3.62 mg/L (1.47-6.02). Antibodies to IFX (ATI) were detected in 14 patients. The predicted median AUC was 28,421 mg/h/L (22,336-36,903). The median individual predicted CL, K10, and t1/2 values were 4.77 mL/kg/day (3.88-5.90), 0.09 days (0.08-0.12), and 12.22 days (9.49-14.87), respectively. IFX Cmin, AUC, CL, and K10 were significantly influenced by ATI and serum albumin concentrations. Moreover, body weight was significantly associated with AUC, CL, and K10. Patients receiving concurrent immunosuppressive therapy had higher Cmin and AUC values and lower CL and K10 values than those treated with IFX monotherapy. We also observed high intrapatient variability in Cmin values during the study period.
In this repeated-measures study in a population of IBD patients, we observed significant associations between ATI, serum albumin concentration, concomitant immunosuppressive therapy, body weight and gender, and IFX Cmin, and CL. The high PK variability observed in this study supports the need for proactive TDM to optimize the use of IFX as early as possible in IBD patients.
The effect of the use of immunomodulatory drugs on the risk of developing hospital-acquired bloodstream infection (BSI) in patients with COVID-19 has not been specifically assessed. We aim to ...identify risk factors for, and outcomes of, BSI among hospitalized patients with severe COVID-19 pneumonia.
We performed a severity matched case–control study (1:1 ratio) nested in a large multicentre prospective cohort of hospitalized adults with COVID-19. Cases with BSI were identified from the cohort database. Controls were matched for age, sex and acute respiratory distress syndrome. A Cox proportional hazard ratio model was performed.
Of 2005 patients, 100 (4.98%) presented 142 episodes of BSI, mainly caused by coagulase-negative staphylococci, Enterococcus faecalis and Pseudomonas aeruginosa. Polymicrobial infection accounted for 23 episodes. The median time from admission to the first episode of BSI was 15 days (IQR 9–20), and the most frequent source was catheter-related infection. The characteristics of patients with and without BSI were similar, including the use of tocilizumab, corticosteroids, and combinations. In the multivariate analysis, the use of these immunomodulatory drugs was not associated with an increased risk of BSI. A Cox proportional hazard ratio (HR) model showed that after adjusting for the time factor, BSI was associated with a higher in-hospital mortality risk (HR 2.59; 1.65–4.07; p < 0.001).
Hospital-acquired BSI in patients with severe COVID-19 pneumonia was uncommon and the use of immunomodulatory drugs was not associated with its development. When adjusting for the time factor, BSI was associated with a higher mortality risk.
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Abstract Objectives Spontaneous bacterial peritonitis is a frequent severe complication in cirrhotic patients with ascites. Carbapenem antibiotics are currently the treatment of choice for patients ...with hospital-acquired or healthcare-related infections. However, there is limited evidence available on the efficacy of ertapenem in cirrhotic patients with spontaneous bacterial peritonitis. As a result, the pharmacokynetics and pharmacodynamics of this antibiotic are still unknown. The objective of this study was to develop and validate measurement procedures based on liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to determine ertapenem concentrations in plasma and ascitic fluid. Methods Samples were pretreated by acetronile protein-precipitation. Chromatographic separation is performed on a C 18 reversed-phase Acquity ® -UPLC ® -BEH TM column (2.1 × 100 mm id, 1.7 µm) using a non-linear gradient of water/acetonitrile containing 0.1 % of formic acid at a flow rate of 0.4 mL/min. Ertapenem and its internal standard (ertapenem-D 4 ) are detected by tandem mass spectrometry using positive electrospray ionization and multiple reaction monitoring, and using 476.2 → 346.0/432.2 as mass transition for ertapenem and 480.2 → 350.0 for its internal standard. Results No significant interferences or carry-over contamination were observed. Imprecisions, absolute relative bias, matrix effects and normalized recoveries were ≤14.5 %, ≤9.3 % (92.8–104.5) % and (98.8–105.8) %, respectively. Chromatographic measurement procedures were linear from (0.50–100) mg/L. Conclusions The measurement procedures based on UHPLC-MS/MS developed and validated in this study could be useful in pharmacokynetic and pharmacodynamic studies in subjects with liver cirrhosis who develop spontaneous bacterial peritonitis treated with ertapenem.
We assessed the antibiotic use in SARS-CoV-2-infected patients during four different waves of the COVID-19 pandemic, as well as its trends over the period and associated risk factors. We performed a ...cross-sectional retrospective analysis nested in a prospectively collected cohort of hospitalized adult patients with COVID-19 at a university hospital in Spain. A total of 2415 patients were included in this study, among whom 1120 corresponded to the first wave. The highest percentage of patients receiving some sort of antibiotic treatment was higher during the first wave (77.6%) than during the others; nevertheless, our calculation of the average DOT (days of antibiotic treatment) per 100 patient days of stay found that the highest antibiotic prescription rate corresponded to the second pandemic wave (61.61 DOT/100 patient days), which was associated with a higher ICU admission rate and a lower SpO
/FiO
ratio at admission. After the second wave, the prescription rates presented a steady downward trend. With regard to the use of specific antibiotic families, amoxicillin/clavulanate was the most used antibiotic in our cohort (14.20 DOT/100 patient days) due to a high prescription rate during the first wave. According to the "AWaRe" WHO classification, antibiotics corresponding to the "Watch" group were the most prescribed (27.92 DOT/100 patient days). The antibiotic use rate fell progressively, but it remained high during all four waves analyzed. In conclusion, antibiotic use was high throughout all the waves that were analyzed, despite a relatively low incidence of bacterial coinfection and superinfection. Efforts should be made to keep antimicrobial stewardship programs active, especially in complicated epidemiological situations, such as the SARS-CoV-2 pandemic.
To evaluate the efficacy and safety of long-term use of tedizolid in osteoarticular infections.
Multicentric retrospective study (January 2017-March 2019) of osteoarticular infection cases treated ...with tedizolid. Failure: clinical worsening despite antibiotic treatment or the need of suppressive treatment.
Cases (
= 51; 59% women, mean age of 65 years) included osteoarthritis (
= 27, 53%), prosthetic joint infection (
= 17, 33.3%), and diabetic foot infections (
= 9, 18%); where, 59% were orthopedic device-related. Most frequent isolates were Staphylococcus spp. (65%,
= 47; S. aureus, 48%). Reasons for choosing tedizolid were potential drug-drug interaction (63%) and cytopenia (55%); median treatment duration was 29 days (interquartile range -IQR- 15-44), 24% received rifampicin (600 mg once daily) concomitantly, and adverse events were scarce (
= 3). Hemoglobin and platelet count stayed stable throughout treatment (from 108.6 g/L to 116.3 g/L,
= 0.079; and 240 × 10
/L to 239 × 10
/L,
= 0.942, respectively), also in the subgroup of cases with cytopenia. Among device-related infections, 33% were managed with implant retention. Median follow-up was 630 days and overall cure rate 83%; among failures (
= 8), 63% were device-related infections.
Long-term use of tedizolid was effective, showing a better safety profile with less myelotoxicity and lower drug-drug interaction than linezolid. Confirmation of these advantages could make tedizolid the oxazolidinone of choice for most of osteoarticular infections.
Voriconazole, an antifungal agent, displays high intra- and inter-individual variability. The predictive pharmacokinetic (PK) index requires a minimum plasma concentration (C
) in patient serum of ...between 1-5.5 mg/L. It is common to encounter fungal infections in patients undergoing extracorporeal membrane oxygenation (ECMO) support, and data regarding voriconazole PK changes during ECMO are scarce. Our study compared voriconazole PKs in patients with and without ECMO support in a retrospective cohort of critically-ill patients. Fifteen patients with 26 voriconazole C
determinations in the non-ECMO group and nine patients with 27 voriconazole C
determinations in the ECMO group were recruited. The ECMO group had lower C
(0.38 ± 2.98 vs. 3.62 ± 3.88,
< 0.001) and higher infratherapeutic C
values (16 vs. 1,
< 0.001) than the non-ECMO group. Multivariate analysis identified ECMO support (-0.668, CI
-0.978--0.358) and plasma albumin levels (-0.023, CI
-0.046--0.001) as risk factors for low C
values. When comparing pre- and post-therapeutic drug optimisation samples from the ECMO group, the dose required to achieve therapeutic C
was 6.44 mg/kg twice a day. Therapeutic drug optimisation is essential to improve target attainment.
Community-acquired pneumonia (CAP) continues to be a major health problem worldwide and is one of the main reasons for prescribing antibiotics. However, the causative agent is often not identified, ...resulting in antibiotic overtreatment, which is a key driver of antimicrobial resistance and adverse events. We aim to test the hypothesis that comprehensive molecular testing, compared with routine microbiological testing, would be effective in reducing antibiotic use in patients with CAP.
We will perform a randomised, controlled, open-label clinical trial with two parallel groups (1:1) at two tertiary hospitals between 2020 and 2022. Non-severely immunosuppressed adults hospitalised for CAP will be considered eligible. Patients will be randomly assigned to receive either the experimental diagnosis (comprehensive molecular testing plus routine microbiological testing) or standard diagnosis (only microbiological routine testing). The primary endpoint will be antibiotic consumption measured as days of antibiotic therapy per 1000 patient-days. Secondary endpoints will be de-escalation to narrower antibiotic treatment, time to switch from intravenous to oral antibiotics, days to reaching an aetiological diagnosis, antibiotic-related side effects, length of stay, days to clinical stability, intensive care unit admission, days of mechanical ventilation, hospital readmission up to 30 days after randomisation and death from any cause by 48 hours and 30 days after randomisation. We will need to include 440 subjects to be able to reject the null hypothesis that both groups have equal days of antibiotic therapy per 1000 patient-days with a probability >0.8.
Ethical approval has been obtained from the Ethics Committee of Bellvitge Hospital (AC028/19) and from the Spanish Medicines and Medical Devices Agency, and it is valid for all participating centres under existing Spanish legislation. Results will be presented at international meetings and will be made available to patients, their caregivers and funders.
ClinicalTrials: NCT04158492. EudraCT: 2018-004880-29.
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