BACKGROUND AND OBJECTIVES: Renal elimination of amikacin and other aminoglycosides is slowed down in sepsis-induced acute kidney injury increasing the risk of adverse effects. Since neutrophil gelatinase-associated lipocalin (NGAL) and aminoglycosides share the mechanisms for renal excretion, the predictive power of NGAL was examined towards the changes in amikacin pharmacokinetics during early endotoxemia in anesthetized Wistar rats. METHODS: Endogenous biomarkers of inflammation and acute kidney injury were assessed including NGAL in saline-injected controls and two groups of rats challenged with an intravenous injection of bacterial lipopolysaccharide (5 mg/kg)-a fluid-resuscitated group (LPS) and a fluid-resuscitated group infused intravenously with 8 μg/kg/h terlipressin (LPS-T). Sinistrin and amikacin were infused to measure glomerular filtration rate (GFR) and amikacin clearance (CLam). The investigations included blood gas analysis, chemistry and hematology tests and assessment of urine output, creatinine clearance (CLcr) and sinistrin clearance (CLsini). RESULTS: Within 3 h of injection, systemic and renal inflammatory responses were induced by lipopolysaccharide. Gene and protein expression of NGAL was increased in the kidneys and the concentrations of NGAL in the plasma (pNGAL) and urine rose 4- to 38-fold (P < 0.01). The decreases in CLam and the GFR markers (CLcr, CLsini) were proportional, reflecting the extent to which endotoxemia impaired the major elimination mechanism for the drug. Terlipressin attenuated lipopolysaccharide-induced renal dysfunction (urine output, CLcr, CLsini) and accelerated CLam. The pNGAL showed a strong association with the CLsini (rs = - 0.77, P < 0.0005). Concerning prediction of CLam, pNGAL was comparable to CLcr (mean error - 24%) and inferior to CLsini (mean error - 6.4%), while the measurement of NGAL in urine gave unsatisfactory results. CONCLUSIONS: During early endotoxemia in the rat, pNGAL has a moderate predictive ability towards CLam. Clinical studies should verify whether pNGAL can support individualized dosing of aminoglycosides to septic patients.
- MeSH
- akutní poškození ledvin krev MeSH
- amikacin krev metabolismus farmakokinetika MeSH
- biologické markery krev MeSH
- cytokiny MeSH
- endotoxemie chemicky indukované MeSH
- hodnoty glomerulární filtrace fyziologie MeSH
- krysa rodu Rattus MeSH
- ledviny patofyziologie MeSH
- lipokalin-2 krev metabolismus moč MeSH
- lipopolysacharidy farmakologie MeSH
- metabolická clearance MeSH
- moč MeSH
- modely u zvířat MeSH
- oligosacharidy farmakokinetika MeSH
- potkani Wistar * MeSH
- prediktivní hodnota testů MeSH
- sepse farmakoterapie metabolismus MeSH
- zánět MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- amikacin MeSH
- biologické markery MeSH
- cytokiny MeSH
- lipokalin-2 MeSH
- lipopolysacharidy MeSH
- oligosacharidy MeSH
- sinistrin MeSH Prohlížeč
This study aimed at investigating variables affecting amikacin pharmacokinetics in order to propose optimal initial dosing in critically ill adult patients treated with once-daily amikacin regimen. Amikacin pharmacokinetics was calculated based on plasma concentrations using one compartmental analysis. Relationships between pharmacokinetic parameters and demographic/clinical data were explored in linear regression models. Simulated dose and dosing intervals were derived from body size descriptors and estimated creatinine clearances for each patient. Amikacin volume of distribution best correlated with body surface area, while amikacin clearance was best predicted by CKD-EPI creatinine clearance. Our study suggests that dose of 517 mg per m2 of body surface area leads to amikacin levels most approaching target peak concentration. Dosing interval calculated as 228.7 × e-3.08× CKD-EPI creatinine clearance (mL s-1) + 15.84 most closely approximated optimal dosing intervals based on individual pharmacokinetics. The dosing nomogram based on CKD-EPI creatinine clearance was designed.
- Klíčová slova
- Amikacin, Body size descriptors, Creatinine clearance, Dosing, Intensive care, Pharmacokinetics,
- MeSH
- amikacin aplikace a dávkování farmakokinetika MeSH
- antibakteriální látky aplikace a dávkování farmakokinetika MeSH
- gramnegativní bakteriální infekce farmakoterapie MeSH
- kritický stav * MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- Názvy látek
- amikacin MeSH
- antibakteriální látky MeSH
Aminoglycosides constitute one of the oldest classes of antimicrobials. Despite their relative toxicity, mainly nephrotoxicity and ototoxicity, aminoglycosides are valuable in current clinical practice. They are bactericidal agents with activity against aerobic gram-negative infections and against gram-positive cocci when added to a cell wall active antimicrobial-based regimen (e.g. betalactams). Aminoglycosides have a concentration-dependent bactericidal effect and a long post antibiotic effect. There is accumulating evidence to show that large, single, daily doses (or more correctly, extended interval dosing) of aminoglycosides is associated with less nephrotoxicity and ototoxicity and comparable, if not superior clinical outcomes than the same total dose administered in small, multiple doses. The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations. A key strategy in minimizing toxicity and optimizing therapy is therapeutic drug monitoring. Key words: aminoglycosides - amikacin - gentamicin - therapeutic monitoring.
- MeSH
- amikacin škodlivé účinky farmakokinetika terapeutické užití MeSH
- antibakteriální látky škodlivé účinky farmakokinetika terapeutické užití MeSH
- gentamiciny škodlivé účinky farmakokinetika terapeutické užití MeSH
- lidé MeSH
- monitorování léčiv * MeSH
- rozvrh dávkování léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- amikacin MeSH
- antibakteriální látky MeSH
- gentamiciny MeSH
BACKGROUND: ECMO (extracorporeal membrane oxygenation) is increasingly used in severe hemodynamic compromise and cardiac arrest (CA). Pulmonary infections are frequent in these patients. Venoarterial (VA) ECMO decreases pulmonary blood flow and antibiotic availability in lungs during VA ECMO treated CA is not known. We aimed to assess early vancomycin, amikacin and gentamicin concentrations in the pulmonary artery as well as tracheal aspirate and to determine penetration ratios of these antibiotics to lung tissue in a pig model of VA ECMO treated CA. METHODS: Twelve female pigs, body weight 51.5 ± 3.5 kg, were subjected to prolonged CA managed by different modes of VA ECMO. Anesthetized animals underwent 15 min of ventricular fibrillation (VF) followed by continued VF with ECMO flow of 100 mL/kg/min. Immediately after institution of ECMO, a 30 min vancomycin infusion (10 mg/kg) was started and amikacin and gentamicin boluses (7.5 and 3 mg/kg, respectively) were administered. ECMO circuit, aortic, pulmonary arterial, and tracheal aspirate concentrations of antibiotics were measured at 30 and 60 min after administration; penetration ratios were calculated. RESULTS: All 30 min antibiotic concentrations and 60 min concentration for gentamicin in the pulmonary artery were no different than the aorta. However, the 60 min pulmonary artery vancomycin and amikacin values were significantly higher than aortic, 19.8 (14.3-21.6) vs. 17.6 (14.2-19.0) mg/L, p = 0.009, and 15.6 mg/L (11.0-18.6) vs. 11.2 (10.4-17.2) mg/L, p = 0.036, respectively. One hour penetration ratios were 18.5% for vancomycin, 34.9% for gentamicin and 38.8% for amikacin. CONCLUSION: In a pig model of VA ECMO treated prolonged CA, despite diminished pulmonary flow, VA ECMO does not decrease early vancomycin, gentamicin, and amikacin concentrations in pulmonary artery. Within 1 h post administration, antibiotics can be detected in tracheal aspirate in adequate concentrations.
- Klíčová slova
- Antibiotic availability, Cardiac arrest, ECMO, Penetration ratio, Pulmonary tissue,
- MeSH
- amikacin farmakokinetika MeSH
- antibakteriální látky farmakokinetika MeSH
- arteria pulmonalis metabolismus MeSH
- časové faktory MeSH
- gentamiciny farmakokinetika MeSH
- mimotělní membránová oxygenace metody MeSH
- modely nemocí na zvířatech MeSH
- plíce metabolismus MeSH
- prasata MeSH
- srdeční zástava terapie MeSH
- tkáňová distribuce MeSH
- vankomycin farmakokinetika MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- amikacin MeSH
- antibakteriální látky MeSH
- gentamiciny MeSH
- vankomycin MeSH
BACKGROUND AND OBJECTIVE: Monitoring of renal function in cystic fibrosis (CF) patients is essential. The dosage regimen of amikacin is regularly modified according to the patient's glomerular filtration rate (GFR). The aim of the study was to evaluate the use of cystatin C (CyC) for monitoring amikacin therapy along with other markers of renal tubular and glomerular function, and damage [N-acetyl-beta-d glucosaminidase (NAG), creatinine level and creatinine clearance]. METHODS: We compared the GFR, estimated from the serum concentrations of creatinine (Cockcroft-Gault formula) and CyC (Grubb's formula). Seventy-one patients (mean age 12 years; range 4-28 years) with CF were treated by intermittent intravenous infusion of amikacin. Tubular nephrotoxicity was investigated by measurement of urine NAG/urine creatinine ratio (U-NAG/U-creatinine). Concentrations of all markers were measured before starting amikacin therapy and at days 3, 5, 7, 10 and 12. Fluorescence polarization analysis, turbidimetry, enzymatic phototometric creatinine deaminase method and fluorimetry were used for determination of serum amikacin, serum CyC, creatinine and urine NAG activity. Receiver operating characteristic (ROC) analysis was performed to assess the influence of GFR estimated from serum creatinine and serum CyC for the prediction of amikacin clearance during aminoglycoside therapy. RESULTS: Significant differences in the rate of U-NAG/U-creatinine were noted before and after treatment with amikacin (P < 0.001). Serum creatinine levels and creatinine clearance at the end of amikacin therapy (12th day) did not show any significant differences in comparison with the levels measured before the start of therapy (0th day). At days 5, 7, 10 and 12, serum CyC levels showed a significant elevation (P < 0.001), and CyC clearance showed a significant decrease (P < 0.001) in comparison with the levels measured at day 0. The ratio of amikacin clearance/creatinine clearance decreased with therapy whereas the amikacin clearance/CyC and amikacin clearance/CyC clearance increased. CONCLUSION: We showed that the rate of U-NAG/U-creatinine is a suitable marker for monitoring tubular nephrotoxicity in CF patients. Serum creatinine and estimated creatinine clearance are modest predictors of GFR in CF patients. CyC appears to be a better marker of GFR than serum creatinine concentration or creatinine clearance in our study. Serum CyC levels and CyC clearance showed greater ability to predict amikacin clearance during therapy than creatinine clearance.
- MeSH
- acetylglukosaminidasa moč MeSH
- amikacin aplikace a dávkování farmakokinetika farmakologie MeSH
- antibakteriální látky aplikace a dávkování farmakokinetika farmakologie MeSH
- biologické markery krev MeSH
- časové faktory MeSH
- cystatin C MeSH
- cystatiny krev MeSH
- cystická fibróza krev farmakoterapie MeSH
- dítě MeSH
- dospělí MeSH
- hodnoty glomerulární filtrace * MeSH
- intravenózní infuze MeSH
- kreatinin krev moč MeSH
- ledviny účinky léků patologie MeSH
- lidé MeSH
- mladiství MeSH
- monitorování léčiv MeSH
- předškolní dítě MeSH
- ROC křivka MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- srovnávací studie MeSH
- Názvy látek
- acetylglukosaminidasa MeSH
- amikacin MeSH
- antibakteriální látky MeSH
- biologické markery MeSH
- CST3 protein, human MeSH Prohlížeč
- cystatin C MeSH
- cystatiny MeSH
- kreatinin MeSH
BACKGROUND: Once-daily administration of aminoglykosides is routinely used, but comparative efficacy data for patients with cystic fibrosis are not available. METHODS AND RESULTS: The aim of the this study was to compare the predicted pharmacodynamic (PD) activity of amikacin at 28 mg/kg/den administered every 24 hod.(q24h), q12h, and q8h. Pharmacokinetic (PK) data were derived from analysis of the amikacin serum concentration from 42 CF children patients. Individual pharmacokinetics values were used to construct serum concentration--versus time curves and to determine various indices (c peak/MIC ratio and time during the concentration was less than the MIC--T < MIC) for all three dose regimens described above. MIC (minimal inhibitory concentration) for Pseudomonas aeruginosa was 4 mg/l. Significantly lower c peak/MIC but shorter T < MIC were noted when regimens of q8h versus q12h (p < 0.001), q8h vs. q24h (p < 0.001) and q12h vs. q24h (p < 0.001) were compared. This analysis suggests that the potential advantage of achieving a greater c peak/MIC with once-daily aminoglycoside administration may be neutralized by the significantly greater T < MIC in CF patients compared with that achieved with multiple-daily-dosing regimens. CONCLUSIONS: Routine use of once daily amikacin administration could not be recommended until the clinical data confirming efficiency of this dose modality are available.
- MeSH
- amikacin aplikace a dávkování farmakokinetika MeSH
- antibakteriální látky aplikace a dávkování farmakokinetika MeSH
- biologické modely MeSH
- cystická fibróza krev mikrobiologie MeSH
- dítě MeSH
- infekce dýchací soustavy komplikace farmakoterapie MeSH
- lidé MeSH
- mladiství MeSH
- počítačová simulace MeSH
- pseudomonádové infekce komplikace farmakoterapie MeSH
- rozvrh dávkování léků MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- amikacin MeSH
- antibakteriální látky MeSH
BACKGROUND: Penetration of antibiotics into the pancreas is considered to be an important criterion in determining the most appropriate antibiotic treatment during severe acute pancreatitis. Our study investigated pancreatic penetration of five antibiotics in rats with and without acute necrotizing pancreatitis (ANP) (non-pancreatitis rats (NR), pancreatitis rats (AP)). METHODS: ANP was induced by intraductal bile acid injection, and 3 h later the antibiotic was administered. In both NR and AP the antibiotic concentrations were evaluated in blood and pancreatic tissue 90 min after antibiotic administration. RESULTS: The tissue/serum (T/S) ratios for NR were 16% with amikacin, 24% with amoxycillin/clavulanic acid, 27% with piperacillin, 59% with ofloxacin, and 108% with cefoperazone. The ratios for AP were 7%, 23%, 26%, 52%, and 70%, respectively. T/S ratios were similar for NR and AP except for amikacin, for which the T/S ratio was lower in AP than in NR (P = 0.02). Pancreatic tissue concentrations of antibiotics with high penetration rates (cefoperazone and ofloxacin) were sufficient to inhibit most of the pathogens expected during acute pancreatitis. The concentrations of the other antibiotics were less than the minimal inhibitory concentrations (MIC) for common potential pathogens in pancreatic infection. CONCLUSIONS: Cefoperazone and ofloxacin showed the best pancreatic penetration of the five antibiotics tested. The high concentrations of these antibiotics in the pancreatic tissue would have enabled efficient antibacterial activity against most of the potential pathogens causing pancreatic infection. An early stage of acute necrotizing pancreatitis did not have a major effect on the pancreatic concentrations of the antibiotics.
- MeSH
- akutní nekrotizující pankreatitida chemicky indukované metabolismus MeSH
- amikacin farmakokinetika MeSH
- amoxicilin farmakokinetika MeSH
- antibakteriální látky farmakokinetika MeSH
- cefoperazon farmakokinetika MeSH
- krysa rodu Rattus MeSH
- kyselina klavulanová farmakokinetika MeSH
- kyselina taurocholová MeSH
- ofloxacin farmakokinetika MeSH
- pankreas metabolismus MeSH
- pankreatická šťáva metabolismus MeSH
- piperacilin farmakokinetika MeSH
- potkani Wistar MeSH
- tkáňová distribuce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- amikacin MeSH
- amoxicilin MeSH
- antibakteriální látky MeSH
- cefoperazon MeSH
- kyselina klavulanová MeSH
- kyselina taurocholová MeSH
- ofloxacin MeSH
- piperacilin MeSH
- MeSH
- amikacin farmakokinetika MeSH
- antibakteriální látky farmakokinetika MeSH
- cystická fibróza komplikace farmakoterapie metabolismus MeSH
- lidé MeSH
- pneumonie komplikace farmakoterapie metabolismus MeSH
- pseudomonádové infekce komplikace farmakoterapie metabolismus MeSH
- tobramycin farmakokinetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- amikacin MeSH
- antibakteriální látky MeSH
- tobramycin MeSH
