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Clinica Chimica Acta; International... Dec 2021Therapeutic drug monitoring (TDM) of β-lactam antibiotics may be used to optimize dosing for patients in the intensive care unit (ICU). A noninvasive matrix such as...
BACKGROUND
Therapeutic drug monitoring (TDM) of β-lactam antibiotics may be used to optimize dosing for patients in the intensive care unit (ICU). A noninvasive matrix such as oral fluid may be interesting in selected patient groups. We compared the oral fluid concentrations of piperacillin and meropenem with the respective unbound and total concentrations in plasma. A secondary objective was to evaluate feasibility of the collection of oral fluid samples in this specific patient population.
METHODS
The study included 20 non-intubated ICU patients, age 22 to 77 y, receiving piperacillin or meropenem via continuous intravenous infusion. The standard protocol consisted of collecting a paired plasma-oral fluid sample for 3 consecutive days. Oral fluid was obtained from the patients using a standardized procedure by spitting in a plastic container after 2 min of gathering oral fluid in the mouth.
RESULTS
Antibiotic concentrations of piperacillin and meropenem are measurable, albeit very low, in unstimulated oral fluid of ICU patients. For piperacillin, a poor correlation was found between oral fluid and both total and unbound plasma concentrations (Spearman's correlation coefficients (Rs) 0.46 and 0.48 respectively). For meropenem this correlation was better (Rs for oral fluid versus total and unbound plasma meropenem concentration 0.92 and 0.93 respectively). Dispersion of antibiotic concentrations was greater in oral fluid than in blood. Collecting oral fluid samples was difficult in non-intubated ICU patients.
CONCLUSIONS
Oral fluid from non-intubated ICU patients, obtained through a standardized procedure, cannot be recommended as an alternative matrix for quantitative meropenem or piperacillin TDM.
Topics: Adult; Aged; Anti-Bacterial Agents; Critical Illness; Humans; Intensive Care Units; Meropenem; Middle Aged; Pilot Projects; Piperacillin; Young Adult
PubMed: 34508687
DOI: 10.1016/j.cca.2021.09.005 -
European Journal of Clinical... Feb 2020We analysed the pharmacokinetics of meropenem and piperacillin-tazobactam in patients undergoing a standardised session of sustained low efficiency haemodiafiltration...
OBJECTIVE
We analysed the pharmacokinetics of meropenem and piperacillin-tazobactam in patients undergoing a standardised session of sustained low efficiency haemodiafiltration (SLED-HDF) to inform the dosing of these drugs in an acute setting.
PARTICIPANTS
Six stable patients with end-stage kidney disease.
METHODS
An open-label pilot pharmacokinetic study of meropenem and piperacillin-tazobactam. SLED-HDF was undertaken for 4 h. Plasma drug concentrations were measured pre- and post-filter and in the effluent at multiple time points. The pharmacokinetic data was analysed using non-compartmental methods. The fraction of time that individual plasma concentration profiles were predicted to remain above the MIC break-points for commonly isolated gram-negative pathogens during a prolonged SLED-HDF session was assessed using two targets; fT > MIC (fraction of time above the MIC) and the more aggressive fT > 4 × MIC (fraction of time above 4 × MIC).
RESULTS
Meropenem total and SLED-HDF clearance ranged from 141 to 180 mL/min and 126-205 mL/min, respectively. Piperacillin total and SLED-HDF clearance values ranged from 131 to 252 mL/min and 135-162 mL/min, respectively. Our results suggest that prolonged SLED-HDF (12 h) will only maintain a sufficient meropenem and piperacillin-tazobactam plasma concentration to achieve a target of fT > MIC for gram-negative pathogens (MIC 2 mg/L-meropenem, 8 mg/L-piperacillin-tazobactam) for less than 40% of the time. Plasma concentrations would be inadequate to achieve the more aggressive target of 100 % fT > 4xMIC target recommended for critically unwell patients.
CONCLUSIONS
The pharmacokinetic data obtained from this pilot study demonstrate significant quantities of meropenem and piperacillin are removed during a SLED-HDF session. This may lead to subtherapeutic concentrations of piperacillin and meropenem over the duration of HDF session.
TRIAL REGISTRATION
Australasian Clinical Trials Registry Network (ACTRN12616000078459).
Topics: Adult; Aged; Anti-Bacterial Agents; Female; Hemodiafiltration; Humans; Kidney Failure, Chronic; Male; Meropenem; Middle Aged; Pilot Projects; Piperacillin, Tazobactam Drug Combination
PubMed: 31814045
DOI: 10.1007/s00228-019-02792-0 -
Antimicrobial Agents and Chemotherapy Mar 2022Clinical studies have reported additive nephrotoxicity associated with the combination of vancomycin (VAN) and piperacillin-tazobactam (TZP). This study assessed...
Clinical studies have reported additive nephrotoxicity associated with the combination of vancomycin (VAN) and piperacillin-tazobactam (TZP). This study assessed differences in glomerular filtration rate (GFR) and urinary biomarkers between rats receiving VAN and those receiving VAN + TZP. Male Sprague-Dawley rats ( = 26) were randomized to receive 96 h of intravenous VAN at 150 mg/kg/day, intraperitoneal TZP at 1,400 mg/kg/day, or VAN + TZP. Kidney function was evaluated using fluorescein-isothiocyanate sinistrin and a transdermal sensor to estimate real-time glomerular filtration rate (GFR). Kidney injury was evaluated via urinary biomarkers, including kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Compared to a saline control, only rats in the VAN group showed significant declines in GFR by day 4 (-0.39 mL/min/100 g body weight; 95% confidence interval [CI], -0.68 to -0.10; = 0.008). When the VAN + TZP and VAN alone treatment groups were compared, significantly higher urinary KIM-1 marginal linear predictions were observed in the VAN alone group on day 1 (18.4 ng; 95% CI, 1.4 to 35.3; = 0.03), day 2 (27.4 ng; 95% CI, 10.4 to 44.3; = 0.002), day 3 (18.8 ng; 95% CI, 1.9 to 35.8; = 0.03), and day 4 (23.2 ng; 95% CI, 6.3 to 40.2; = 0.007). KIM-1 was the urinary biomarker that most correlated with decreasing GFR on day 3 (Spearman's rho, -0.45; = 0.022) and day 4 (Spearman's rho, -0.41; = 0.036). Kidney function decline and increased KIM-1 were observed among rats that received VAN only but not those that received TZP or VAN + TZP. The addition of TZP to VAN does not worsen kidney function or injury in our translational rat model.
Topics: Acute Kidney Injury; Animals; Anti-Bacterial Agents; Biomarkers; Drug Therapy, Combination; Male; Piperacillin, Tazobactam Drug Combination; Rats; Rats, Sprague-Dawley; Retrospective Studies; Vancomycin
PubMed: 35007142
DOI: 10.1128/aac.02132-21 -
Frontiers in Cellular and Infection... 2022has recently gained global attention and is emerging as a cause of life-threatening nosocomial infections. The present study aimed to investigate the association...
has recently gained global attention and is emerging as a cause of life-threatening nosocomial infections. The present study aimed to investigate the association between antimicrobial resistance and the ability to form biofilm among isolated from hospitalized patients in China. Over 10 years, a total of 197 non-duplicate strains were collected. Antibiotic susceptibility was determined by the standard agar dilution method as a reference assay according to the Clinical and Laboratory Standards Institute. The biofilm formation ability was assessed using a culture microtiter plate method, which was determined using a crystal violet assay. Culture plate results were cross-checked by scanning electron microscopy imaging analysis. Among the 197 isolates, all were multidrug-resistant, and 20 were extensively drug-resistant. Clinical showed high resistance to current antibiotics, and 99% of the isolates were resistant to at least seven antibiotics. The resistance rate for aztreonam, ceftazidime, imipenem, meropenem, trimethoprim-sulfamethoxazole, cefepime, and tetracycline was high as 100%, 99%, 99%, 99%, 99%, 95%, and 90%, respectively. However, the isolates exhibited the highest susceptibility to minocycline (100%), doxycycline (96%), and rifampin (94%). The biofilm formation results revealed that all strains could form biofilm. Among them, the proportions of strong, medium, and weak biofilm-forming strains were 41%, 42%, and 17%, respectively. Furthermore, the strains forming strong or moderate biofilm presented a statistically significant higher resistance than the weak formers (p < 0.05), especially for piperacillin, piperacillin-tazobactam, cefepime, amikacin, and ciprofloxacin. Although was notoriously resistant to large antibiotics, minocycline, doxycycline, and rifampin showed potent activity against this pathogen. The data in the present report revealed a positive association between biofilm formation and antibiotic resistance, which will provide a foundation for improved therapeutic strategies against infections in the future.
Topics: Anti-Bacterial Agents; Biofilms; Cefepime; Doxycycline; Flavobacteriaceae; Humans; Minocycline; Piperacillin; Rifampin
PubMed: 35967866
DOI: 10.3389/fcimb.2022.953780 -
Cancer Reports (Hoboken, N.J.) Oct 2022Children with febrile neutropenia commonly exhibit alterations of pharmacokinetic (PK) parameters, leading to decreased β-lactam concentrations.
BACKGROUND
Children with febrile neutropenia commonly exhibit alterations of pharmacokinetic (PK) parameters, leading to decreased β-lactam concentrations.
AIMS
This study evaluated piperacillin PK and probability of target attainment (PTA) with continuous infusion of piperacillin-tazobactam, in order to optimize the dosing regimen.
METHODS
This prospective PK study included children with cancer, aged 1-17 years, who were treated with piperacillin-tazobactam for suspected or verified infection. A piperacillin-tazobactam loading dose (100 mg/kg) was administered followed by continuous infusion (300 mg/kg/day). The unbound fraction of piperacillin was quantified by high-performance liquid chromatography and PK were described using population PK modeling. PK data was used to update and extend a previous PK model built on data following intermittent administration. Monte Carlo simulations were performed to assess PTA for targets of 100% time above the minimum inhibitory concentration (100% fT > MIC) and 50% fT > 4xMIC.
RESULTS
We included 68 fever episodes among 38 children with a median (IQR) age of 6.5 years and body weight of 27.4 kg (15.1-54.0). A three-compartment model adequately described the concentration-time data. Median (95% confidence interval) estimates for clearance and piperacillin concentration at steady state were 14.2 L/h/70 kg (13.0; 15.3) and 47.6 mg/L (17.2; 129.5), respectively. Body weight or lean body weight was significantly associated with the PK parameters, and body weight was integrated in the final PK model. Based on piperacillin exposure, continuous infusion was the only dosing regimen to achieve optimal PTA for the P. aeruginosa breakpoint (16 mg/L) with the target of 100% fT > MIC, and a daily dose of 300 mg/kg reached optimal PTA. The strict target of 50% fT > 4xMIC (64 mg/L) was not feasibly attained by any dosing regimen at recommended doses.
CONCLUSION
Unlike conventional piperacillin intermittent administration and extended infusion regimens, continuous infusion allows the target of 100% fT > MIC to be reached for children with febrile neutropenia.
Topics: Anti-Bacterial Agents; Body Weight; Child; Febrile Neutropenia; Fever; Humans; Neoplasms; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies
PubMed: 34796702
DOI: 10.1002/cnr2.1585 -
Clinical Infectious Diseases : An... Oct 2021Empiric antimicrobial therapy for healthcare-acquired infections often includes vancomycin plus an anti-pseudomonal beta-lactam (AP-BL). These agents vary in risk for...
BACKGROUND
Empiric antimicrobial therapy for healthcare-acquired infections often includes vancomycin plus an anti-pseudomonal beta-lactam (AP-BL). These agents vary in risk for adverse events, including acute kidney injury (AKI) and Clostrioides difficile infection (CDI). Studies have only examined these risks separately; thus, our objective was to evaluate AKI and CDI risks simultaneously with AP-BL in the same patient cohort.
METHODS
This retrospective cohort study included 789 200 Veterans Health Administration medical admissions from 1 July 2010 through 30 June 2016. The antimicrobials examined were vancomycin, cefepime, piperacillin/tazobactam, and meropenem. Cox proportional hazards regression was used to contrast risks for AKI and CDI across individual target antimicrobials and vancomycin combination therapies, including adjustment for known confounders.
RESULTS
With respect to the base rate of AKI among patients who did not receive a target antibiotic (4.6%), the adjusted hazards ratios for piperacillin/tazobactam, cefepime, and meropenem were 1.50 (95% CI: 1.43-1.54), 1.00 (.95-1.05), 0.92 (.83-1.01), respectively. Co-administration of vancomycin increased AKI rates (data not shown). Similarly, against the base rate of CDI (0.7%), these ratios were 1.21 (1.07-1.36), 1.89 (1.62-2.20), and 1.99 (1.55-2.56), respectively. Addition of vancomycin had minimal impact on CDI rates (data not shown).
CONCLUSIONS
Piperacillin/tazobactam increased AKI risk, which was exacerbated by concurrent vancomycin. Cefepime and meropenem increased CDI risk relative to piperacillin/tazobactam. Clinicians should consider the risks and benefits of AP-BL when selecting empiric regimens. Further well-designed studies evaluating the global risks of AP-BL and patient specific characteristics that can guide empiric selection are needed.
Topics: Acute Kidney Injury; Anti-Bacterial Agents; Cefepime; Clostridioides; Drug Therapy, Combination; Humans; Meropenem; Piperacillin; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Vancomycin
PubMed: 33382398
DOI: 10.1093/cid/ciaa1902 -
Antimicrobial Agents and Chemotherapy Sep 2022Carbapenems are recommended for the treatment of urosepsis caused by extended-spectrum β-lactamase (ESBL)-producing, multidrug-resistant Escherichia coli however, due...
Pharmacodynamics of Piperacillin-Tazobactam/Amikacin Combination versus Meropenem against Extended-Spectrum β-Lactamase-Producing Escherichia coli in a Hollow Fiber Infection Model.
Carbapenems are recommended for the treatment of urosepsis caused by extended-spectrum β-lactamase (ESBL)-producing, multidrug-resistant Escherichia coli however, due to selection of carbapenem resistance, there is an increasing interest in alternative treatment regimens including the use of β-lactam-aminoglycoside combinations. We compared the pharmacodynamic activity of piperacillin-tazobactam and amikacin as mono and combination therapy versus meropenem monotherapy against extended-spectrum β-lactamase (ESBL)-producing, piperacillin-tazobactam resistant E. coli using a dynamic hollow fiber infection model (HFIM) over 7 days. Broth-microdilution was performed to determine the MIC of E. coli isolates. Whole genome sequencing was conducted. Four E. coli isolates were tested in HFIM with an initial inoculum of ~10 CFU/mL. Dosing regimens tested were piperacillin-tazobactam 4.5 g, 6-hourly, plus amikacin 30 mg/kg, 24-hourly, as combination therapy, and piperacillin-tazobactam 4.5 g, 6-hourly, amikacin 30 mg/kg, 24-hourly, and meropenem 1 g, 8-hourly, each as monotherapy. We observed that piperacillin-tazobactam and amikacin monotherapy demonstrated initial rapid bacterial killing but then led to amplification of resistant subpopulations. The piperacillin-tazobactam/amikacin combination and meropenem experiments both attained a rapid bacterial killing (~4-5 log) within 24 h and did not result in any emergence of resistant subpopulations. Genome sequencing demonstrated that all ESBL-producing E. coli clinical isolates carried multiple antibiotic resistance genes including , , , , and . These results suggest that the combination of piperacillin-tazobactam/amikacin may have a potential role as a carbapenem-sparing regimen, which should be tested in future urosepsis clinical trials.
Topics: Amikacin; Anti-Bacterial Agents; Carbapenems; Escherichia coli; Meropenem; Microbial Sensitivity Tests; Piperacillin; Piperacillin, Tazobactam Drug Combination; beta-Lactamases; beta-Lactams
PubMed: 35924928
DOI: 10.1128/aac.00162-22 -
International Journal of Antimicrobial... Sep 2020To describe the adsorption of ticarcillin and piperacillin on to polyethersulfone (PES) membranes using the recirculation function on an ex-vivo renal replacement...
OBJECTIVES
To describe the adsorption of ticarcillin and piperacillin on to polyethersulfone (PES) membranes using the recirculation function on an ex-vivo renal replacement circuit.
METHODS
Low (4-8 mg) or high (35-45 mg) doses of ticarcillin and low (4-8 mg) or high (70-80 mg) doses of piperacillin were added to 1 L of human blood-crystalloid mixture and circulated around an ex-vivo modified continuous renal replacement therapy machine at three different blood flow settings (150, 300 and 450 mL/min). Plasma samples were collected from the pre-filter port of the haemodiafilter circuit at consecutive timepoints for a total duration of 4 h. Plasma samples were measured using a validated ultra high performance liquid chromatography-tandem mass spectrometry method.
RESULTS
Eighty-one samples including both drugs were collected from 18 experimental runs. Overall, the percentage of piperacillin adsorption for the low and high doses ranged from 21.3% to 27.1% and from 11.5% to 23%, and the percentage of ticarcillin adsorption for the low and high doses ranged from 4.2% to 14.3% and from 3.7% to 15.1%, respectively. The low dose of piperacillin consistently yielded more than 20% adsorption of dose for all blood flow rates. This decreased with high blood flow rates when the high dose of piperacillin was used. Ticarcillin generally displayed ≤5% adsorption, with the exceptions being the high dose at 150 mL/min and the low dose at 300 mL/min, which displayed ~15% adsorption.
CONCLUSIONS
Adsorption of both drugs tended to be higher at the lowest blood flow rates and lowest doses. This is likely due to saturation of parts of the filter that have a chemical attraction to both piperacillin and ticarcillin. At low doses at all three blood flow rates, piperacillin demonstrated >20% adsorption, whereas ticarcillin tended to have low rates (up to ~≤15%) of adsorption on to PES membrane filters.
Topics: Adsorption; Anti-Bacterial Agents; Blood Flow Velocity; Hemodiafiltration; Humans; Membranes, Artificial; Piperacillin; Polymers; Renal Replacement Therapy; Sulfones; Ticarcillin
PubMed: 32590056
DOI: 10.1016/j.ijantimicag.2020.106058 -
Therapeutic Drug Monitoring Feb 2020The mortality rate of patients with a drug-resistant bacterial infection is high, as are the associated treatment costs. To overcome these issues, optimization of the...
BACKGROUND
The mortality rate of patients with a drug-resistant bacterial infection is high, as are the associated treatment costs. To overcome these issues, optimization of the available therapeutic options is required. Beta-lactams are time-dependent antibiotics and their efficacy is determined by the amount of time the free concentration remains above the minimum inhibitory concentration. Therefore, the aim of this study was to assess the extent and variability of protein binding for meropenem, cefepime, and piperacillin.
METHODS
Plasma samples for the analysis of meropenem, cefepime, and piperacillin were collected from patients admitted to a tertiary care hospital as part of the standard care. The bound and unbound drug fractions in the samples were separated by ultrafiltration. Validated liquid chromatography-tandem mass spectrometry assays were used to quantify the total and free plasma concentrations, and the protein binding was determined.
RESULTS
Samples from 95 patients were analyzed. The median (range) age of patients was 56 years (17-87) and the median (range) body mass index was 25.7 kg/m (14.7-74.2). Approximately 59% of the patients were men. The median (range) unbound fraction (fu) was 62.5% (41.6-99.1) for meropenem, 61.4% (51.6-99.2) for cefepime, and 48.3% (39.4-71.3) for piperacillin. In the bivariate analysis, as the total meropenem concentration increased, the fu increased (r = 0.37, P = 0.045). A decrease in piperacillin fu was observed as the albumin concentration increased (r = -0.56, P = 0.005).
CONCLUSIONS
The average fu values were lower than those reported in the literature. There was also a large variability in fu; hence, it should be considered when managing patients administered with these drugs through direct measurements of free drug concentrations.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Infections; Cefepime; Drug Monitoring; Female; Humans; Male; Meropenem; Middle Aged; Piperacillin; Protein Binding; Young Adult
PubMed: 31318843
DOI: 10.1097/FTD.0000000000000675 -
European Journal of Drug Metabolism and... May 2021Standard piperacillin-tazobactam (P-T) dosing may be suboptimal in obesity, but high-dose regimens have not been studied. We prospectively evaluated the pharmacokinetics... (Clinical Trial)
Clinical Trial
BACKGROUND AND OBJECTIVE
Standard piperacillin-tazobactam (P-T) dosing may be suboptimal in obesity, but high-dose regimens have not been studied. We prospectively evaluated the pharmacokinetics and pharmacodynamics of standard- and high-dose P-T in obese adult inpatients.
METHODS
Those receiving standard-dose P-T with BMI ≥ 30 kg/m weighing 105-139 kg or ≥ 140 kg were given up to 6.75 g or 9 g every 6 h, respectively. Patients were monitored closely for safety. Elimination phase blood samples were drawn for 28 patients on standard and high doses to calculate the pharmacokinetic values using a one-compartment model. The likelihood of pharmacodynamic target attainment (100% fT > 16/4 mg/L) on various P-T regimens was calculated using each patient's own pharmacokinetic values.
RESULTS
Piperacillin and tazobactam half-lives ranged from 0.5-10.6 to 0.9-15.0 h, while volumes of distribution ranged from 13.6-54.8 to 11.5-60.1 L, respectively. Predicted dose requirements for target attainment ranged from 2.25 g every 6 h in hemodialysis patients to a 27 g/24-h continuous infusion in a patient with a short P-T half-life. An amount of 4.5 g every 6 h would have met the target for only 1/12 (8%) patients with creatinine clearance ≥ 80 mL/min and 13/28 (46%) for all enrolled patients. One patient (3%) experienced an adverse event deemed probably related to high-dose P-T.
CONCLUSION
Some patients required high P-T doses for target attainment, but dosing requirements were highly variable. Doses up to 6.75 g or 9 g every 6 h may be tolerable; however, studies are needed to see if high dosing, prolonged infusions, or real-time therapeutic drug monitoring improves outcomes in obese patients. CLINICAL TRIAL REGISTRATION (CLINICALTRIALS.GOV): NCT01923363.
Topics: Adult; Aged; Anti-Bacterial Agents; Creatinine; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Middle Aged; Models, Biological; Obesity; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Renal Dialysis; Tissue Distribution; Young Adult
PubMed: 33743171
DOI: 10.1007/s13318-021-00677-1