PHARMECMO: Therapeutic drug monitoring and adequacy of current dosing regimens of antibiotics in patients on Extracorporeal Life Support.

INTRODUCTION: Optimisation of antibiotic therapy for extracorporeal membrane oxygenation (ECMO) patients remains a pharmacological challenge. The objective of this study was to observe the plasma concentrations of commonly used antibiotics in intensive care for patients treated with extracorporeal membrane oxygenation. PATIENTS AND METHODS: The PHARMECMO study was a pilot, prospective study, conducted in a cardiac surgery intensive care unit. Every adult patient under ECMO support, with known or suspected sepsis and receiving antibiotic therapy, was eligible for inclusion. Plasma concentrations of antibiotics were determined by a combination of liquid chromatography and mass spectrometry. RESULTS: Forty-four eligible patients were enrolled for 68 inclusions on a twelve-month period. For the association piperacillin-tazobactam (n=19), 68.7% of CT50 and 93.7% of Cmin reached the pharmacokinetic goals defined (64 mg.L-1 for CT50 and 16 mg.L-1 for Cmin). For cefotaxime (n=12), the pharmacokinetic goals (4 mg.L-1 for CT50 and 1 mg.L-1 for Cmin) were achieved in 100% of the cases for CT50 and in 81.8% of the cases for Cmin. Regarding imipenem (n=10), the pharmacokinetic goals were 16 mg.L-1 for CT50 and 4 mg.L-1 for Cmin. Only one CT50 was above 16 mg.L-1. For Cmin, 60% of the doses did not reach the target concentration. In our 10 patients, only one patient was considered as reaching the pharmacokinetic goals. Finally, for amikacin (n=6), four Cmax (66.7%) were infra-therapeutics for a target between 60 and 80 mg.L-1. CONCLUSION: These preliminary results suggest that therapeutic drug monitoring could optimise the achievement of pharmacokinetic objectives associated with an effective antibiotic therapy. For most patients, the recommended doses of imipenem and amikacin did not achieve the pK targets.

Pharmacokinetics of intravenous gentamicin in healthy young-adult compared to aged alpacas.

The study objective was to evaluate the effects of age on aminoglycoside pharmacokinetics in eight young-adult (<4 years) and eight aged (≥14 years) healthy alpacas, receiving a single 6.6 mg/kg intravenous gentamicin injection. Heparinized plasma samples were obtained at designated time points following drug administration and frozen at -80°C until assayed by a validated immunoassay (QMS® ). Compartmental and noncompartmental analyses of gentamicin plasma concentrations versus time were performed using WinNonlin (v6.4) software. Baseline physical and hematological parameters were not significantly different between young and old animals with the exception of sex. Data were best fitted to a two-compartment pharmacokinetic model. The peak drug concentration at 30 min after dosing (23.8 ± 2.1 vs. 26.1 ± 2 µg/ml, p = .043) and area under the curve (70.4 ± 10.5 vs. 90.4 ± 17.6 µg hr/ml, p = .015) were significantly lower in young-adult compared to aged alpacas. Accordingly, young alpacas had a significantly greater systemic clearance than older animals (95.5 ± 14.4 and 75.6 ± 16.1 ml hr-1 kg-1 ; p = .018), respectively). In conclusion, a single 6.6 mg/kg intravenous gentamicin injection achieves target blood concentrations of >10 times the MIC of gentamicin-susceptible pathogens with MIC levels ≤2 µg/ml, in both young-adult and geriatric alpacas. However, the observed reduction in gentamicin clearance in aged alpacas may increase their risk for gentamicin-related adverse drug reactions.

The Efficacy of a Novel Surgical Device in Preventing Intraoperative Wound Contamination in an In Vivo Porcine Model.

BACKGROUND: Surgical site infections (SSIs) remain a morbid and costly complication in abdominal surgery. Topical antibiotic delivery via intraoperative irrigation and barrier wound protection are strategies for preventing SSI. We tested the safety and efficacy of a novel wound protector device with an integrated fluid irrigation platform in a porcine model. METHODS: A simulated colorectal resection model was designed and performed on adult female pigs with a standardized concentration of 109 colony-forming units (CFU) of Escherichia coli administered to the wound site in 10 mL of normal saline (n = 7). The device was tested intraoperatively with and without irrigation with gentamicin-containing irrigant solution. Swab and tissue samples were obtained in addition to peripheral blood samples. Quantitative culture analysis was performed in addition to histological and immunohistochemical analysis and gentamicin concentration measurements. RESULTS: There were no adverse events observed in the animals. Tissue protected by the device yielded exponentially lower levels of E. coli growth compared to exposed tissue, with a mean 1 × 102 CFU/swab. Use of the device, both with and without irrigation, was associated with an exponential reduction in quantitative bacterial load compared to the control wounds with no device, with limited growth after wound closure in the pigs receiving irrigation. Histology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining analysis revealed no significant damage to tissue. Serum gentamicin levels remained below the clinical threshold and decreased over time. CONCLUSIONS: This in vivo study suggests safety and efficacy of a novel device for the prevention of intraoperative wound contamination.

Parámetros farmacocinéticos de gentamicina en recién nacidos de término: ¿Es necesario monitorizar en forma sistemática sus concentraciones plasmáticas? / Gentamicin pharmacokinetics in term newborn: ¿Is it necessary to systematically monitor plasmatic levels?

Background: Gentamicin is indicated as empiric treatment for neonatal sepsis. Plasmatic levels dosification of gentamicin is a common practice. The relationship between peak plasma concentration (Cmáx) with minimum inhibitory concentration (MIC) (Cmáx/MIC) is the parameter that best predicts treatment efficacy. Aim: To determine pharmacokinetics of gentamicin in term newborn infants. Methods: Term newborn infants receiving gentamicin, without critical illness in which plasmatic levels of gentamicin was performed were included. Elimination clearance (Cl) elimination half-life (t½) and volume of distribution (Vd) were calculated. In each case the value of Cmax/MIC parameter was calculated, considering a MIC value of 1 μg/mL for Escherichia coli. Results: Thirteen newborns were included. The mean PK values were Cl: 0.26 mL/hour, Vd: 0.54 L/kg and t½: 6.8 h. Cmax/MIC was > 8 in 6 newborns. Conclusions: Pharmacokinetic parameters of gentamicin are predictable in term newborn infants. With gentamicin doses normally used Cmax/MIC values reached 8 in 6 newborns. It is necessary to review the usefulness of plasma drug monitoring and gentamicin dosage in this group of newborns.

Introducción: Gentamicina es utilizada como tratamiento empírico en la sepsis neonatal. El monitoreo de su concentración plasmática es una práctica frecuente. La relación entre la concentración plasmática máxima (Cmax) y la concentración inhibitoria mínima (Cmax/ CIM) es el parámetro que mejor predice la eficacia. Objetivo: Determinar los parámetros farmacocinéticos (FC) de gentamicina en recién nacidos (RN) de termino. Material y Métodos: Se incluyeron RN de término, sin enfermedad crítica, en tratamiento con gentamicina (4 mg/kg/24 h) en los que se realizó monitoreo de su concentración plasmática. Se determinaron: clearence de eliminación (Cl), vida media de eliminación (t½) y volumen de distribución (Vd). Se estimó la Cmax/CIM, considerando una CIM de 1 μg/mL para Escherichia coli. Resultados: Participaron 13 RN. La media de Cmax fue 8,19 μg/mL y de Cmin 0,73 μg/mL. La media de los parámetros farmacocinéticos fue: Cl 0,26 mL/h, Vd 0,54 L/kg, t½ 6,8 h. La razón Cmáx/CIM fue ≥ 8 en 6 de los 13 RN. Conclusiones: Los parámetros FC de gentamicina en RN de término, sin enfermedad crítica, son predecibles. La posología habitual no permitió obtener valores de Cmax/CIM > 8 en todos los casos. Es necesario revisar la necesidad de monitorizar su concentración plasmática en forma sistemática y la posología de gentamicina en este grupo de pacientes.

Gentamicin for prevention of intraoperative mesh contamination: demonstration of high bactericide effect (in vitro) and low systemic bioavailability (in vivo).

INTRODUCTION: Mesh infection is a severe complication after incisional hernia repair and occurs in 1-3 % of all open mesh implantations. For this reason, topical antimicrobial agent applied directly to the mesh is often used procedure. So far, however, this procedure lacks a scientific basis. MATERIALS AND METHODS: Two different meshes (Parietex™, Covidien; Ultrapro™, Ethicon Johnson & Johnson) were incubated with increasing amounts of three different Staphylococcus aureus strains (ATCC 25923; Mu50; ST239) with or without gentamicin and growth ability were determined in vitro. To further address the question of the systemic impact of topic gentamicin, serum levels were analyzed 6 and 24 h after implantation of gentamicin-impregnated multifilament meshes in 19 patients. RESULTS: None of the gentamicin-impregnated meshes showed any bacterial growth in vitro. This effect was independent of the mesh type for all the tested S. aureus strains. In the clinical setting, serum gentamicin levels 6 h after implantation of the gentamicin-impregnated meshes were below the through-level (range 0.4-2.9 mg/l, mean 1.2 ± 0.7 mg/l). After 24 h the gentamicin serum levels in all patients had declined 90-65 % of the 6 h values. CONCLUSION: Local application of gentamicin to meshes can completely prevent the growth of even gentamicin-resistant S. aureus strains in vitro. The systemic relevance of gentamicin in the clinical controls showed to be very low, without reaching therapeutic concentrations.

The impact of frailty on pharmacokinetics in older people: using gentamicin population pharmacokinetic modeling to investigate changes in renal drug clearance by glomerular filtration.

PURPOSE: Frailty, a multifactorial biological syndrome characterized by a cumulative dysregulation of physiological processes, is associated with changes in pharmacokinetics and pharmacodynamics. The aim of this study was to quantify the effect of frailty on glomerular filtration of drugs, using the probe drug gentamicin. METHODS: Gentamicin concentrations and clinical data including the Reported Edmonton Frail Scale score were pooled from two prospective observational inpatient studies, one on prophylactic gentamicin for urologic surgery and one on therapeutic gentamicin for the empiric treatment of sepsis. Population pharmacokinetic modeling was performed using non-linear mixed effects modeling (NONMEM program) to determine the impact of frailty on gentamicin clearance. RESULTS: A one-compartment linear pharmacokinetic model best described the data and the addition of frailty to the model reduced the random variability in gentamicin clearance by 12 % after adjustment for renal function (estimated creatinine clearance using lean body weight) and lean body weight. Frail patients had an approximately 12 % lower (bootstrapping results: 14 % median) gentamicin clearance than non-frail patients (calculated as a fractional effect of frailty). CONCLUSIONS: Frailty may independently predict reduced clearance of gentamicin in older patients. Frailty could be considered in the development of dosing guidelines for drugs that undergo significant excretion through glomerular filtration.

Intra-articular pharmacokinetics of a gentamicin impregnated collagen sponge in the canine stifle: an experimental study.

OBJECTIVE: To investigate local and systemic pharmacokinetics of gentamicin after intra-articular implantation of a gentamicin impregnated collagen sponge (GICS) in the inflamed canine joint. STUDY DESIGN: Descriptive repeated measures experimental study. ANIMALS: Dogs (n = 9). METHODS: Stifle joint inflammation was caused by urate injection. Twenty-four hours later a GICS (gentamicin dose, 6 mg/kg) was arthroscopically implanted. Synovial fluid and plasma gentamicin concentrations were measured for 14 days after implantation, and pharmacokinetic parameters modeled using statistical moment analyses. RESULTS: Intra-articular gentamicin concentrations fell to sub-MIC for Staphylococcus sp. (4 µg/mL) by 22.4 hours (95% CI: 18.6-26.2) after sponge implantation. Cmax synovial was 2397 µg/mL (95%CI: 1161-3634 µg/mL) at 1.2 hours (95%CI: 0.5-1.8 hours). Plasma gentamicin concentrations achieved levels of Cmax plasma = 8.0 µg/mL (95%CI: 6.1-10.0 µg/mL) at 1.5 hours (95%CI: 0.8-2.1) after GICS placement and fell below target trough of 2.0 µg/mL by 5.6 hours (95%CI: 4.7-6.5 hours) after GICS placement. CONCLUSIONS: Intra-articular gentamicin concentration after GICS placement at an IV-equivalent dose reached high levels and declined rapidly. The maximum plasma levels attained were ∼1/3 of the recommended sub-toxic target for people after parenteral gentamicin administration.

Comparison of inhalation toxicity studies of gentamicin in rats and dogs.

Nebulized gentamicin solution was administered to rats (nose-only) and dogs (face mask) for 14 days with a 14-day recovery period. Control groups of each were exposed to saline aerosols. Mean estimated inhaled lung doses of gentamicin were 39, 123 and 245 mg/kg for rats (deposited doses 6, 17 and 34 mg/kg) over 30, 90 and 180 min, respectively. Since dogs do not tolerate exposures as long as rats, inhaled lung doses were limited to 7, 14 and 41 mg/kg (deposited doses of 1, 3 and 8 mg/kg) over 15, 30 and 60 min. Comparable doses were achieved at the low dose for rats and high dose for dogs. Serum AUCs (14 ± 2 µg/mL h (mean ± SD) at 6 mg/kg in rats and 11 ± 7 µg/mL h at 8 mg/kg in dogs) showed comparable exposure between the two, implying similar absorbed doses and confirming similar deposited lung doses. Rat exposures resulted in dose-related lung pathology (including low dose) manifested as upper respiratory tract irritant reactions with alveolar histiocytosis, inflammation, airway epithelial metaplasia and lymphomegaly in lung tissue. This was associated with high lung tissue gentamicin levels 24 h post-dose on Day 14 (375 ± 33 µg/g at deposited dose of 6 mg/kg). Dose-related kidney tubular necrosis (a well-known toxicity of parenteral gentamicin) was observed, but no test-article related effects on lung histopathology in dogs (even at highest deposited dose of 8 mg/kg) and low levels of lung tissue gentamicin (42 ± 11 µg/g) 24 h post-dose on Day 14.

Effects of obesity and sex on antimicrobial pharmacokinetics and acute kidney injury: validation of a preclinical model.

Obese patients may be at a greater risk for acute kidney injury (AKI) with the use of certain antimicrobial agents that are dosed by weight. Current preclinical models of AKI utilize the male rat within a narrow weight range that limits extrapolation of the generated results. We evaluated the pharmacokinetics and AKI potential of gentamicin in 14-week-old diet-induced obesity-prone (n = 40) and obesity-resistant (n = 40) rats of both sexes. Single daily doses of gentamicin (12.5, 18.75, or 25 mg/kg of body weight) or saline (control) were administered intraperitoneally for 14 doses. Blood samples were collected after doses 1, 7, and 14, assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and analyzed using a nonparametric population pharmacokinetic approach for gentamicin. Urine was collected after doses 1, 3, and 5 and assayed for kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) and normalized to creatinine (Cr) values. Histology was performed on all animals, and the degree of proximal tubular injury was graded. The mean (minimum, maximum) weight of the rats was 330 (136, 580) g. NGAL/Cr predicted AKI better than did KIM-1/Cr and was detectable in male rats after dose 1 and in obesity-prone female rats after dose 5. Proximal tubular injury by histology was significantly higher in male than in female rats. A significant relationship between the gentamicin area under the curve from zero to 24 hours (AUC(0-24)) estimates and the maximum NGAL/Cr ratio was observed. This preclinical model has the potential to aid with dose extrapolation for body size and improve assessment of the toxicology potential of antimicrobials in development.

In vitro and in vivo characteristics of gentamicin-supplemented polyvinylidenfluoride mesh materials.

To reduce infection rates after mesh implantation antibiotic-coated meshes were designed. The aim of the study was to analyze biocompatibility and in vitro efficiency of a modified gentamicin-supplemented polyvinylidenfluoride mesh. Twenty rats were randomized to two groups (PVDF group and Genta group). Mesh material was implanted subcutaneously. Blood samples were taken to determine the gentamicin serum concentration. Seven and 90 days after mesh implantation, animals were euthanized. The inflammatory tissue response was characterized by analyzing the foreign body granuloma. Cellular immune response was analyzed by immunohistochemical investigations. The collagen type I/III ratio was estimated by crosspolarization microscopy. In vitro agar diffusion test, suspension test, and gentamicin release were characterized. Agar diffusion and suspension test showed efficient antibiotic effects of the mesh in vitro. Serum concentrations of gentamicin showed a peak value 1 h postoperatively with a decline within the next day. The total size of the granuloma was significantly smaller in the Genta group compared to the PVDF group at both points of time. Except of a short period of increased expression of CD68 in the Genta group after 7 days, no further difference was found analyzing cellular immune response. The collagen type I/III ratio was widely constant analyzing the two mesh types without significant differences comparing both mesh materials. A significantly decreased foreign body granuloma formation compared to the pure PVDF mesh group was found. In vitro analysis showed efficient antibiotic effects of the Gentamicin supplementation compared to the pure PVDF mesh.

Efficacy of ciprofloxacin-gentamicin combination therapy in murine bubonic plague.

Potential benefits of combination antibiotic therapy for the treatment of plague have never been evaluated. We compared the efficacy of a ciprofloxacin (CIN) and gentamicin (GEN) combination therapy with that of each antibiotic administered alone (i) against Yersinia pestis in vitro and (ii) in a mouse model of bubonic plague in which animals were intravenously injected with antibiotics for five days, starting at two different times after infection (44 h and 56 h). In vitro, the CIN+GEN combination was synergistic at 0.5x the individual drugs' MICs and indifferent at 1x- or 2x MIC. In vivo, the survival rate for mice treated with CIN+GEN was similar to that observed with CIN alone and slightly higher than that observed for GEN alone 100, 100 and 85%, respectively when treatment was started 44 h post challenge. 100% of survivors were recorded in the CIN+GEN group vs 86 and 83% in the CIN and GEN groups, respectively when treatment was delayed to 56 h post-challenge. However, these differences were not statistically significant. Five days after the end of treatment, Y. pestis were observed in lymph nodes draining the inoculation site (but not in the spleen) in surviving mice in each of the three groups. The median lymph node log(10) CFU recovered from persistently infected lymph nodes was significantly higher with GEN than with CIN (5.8 vs. 3.2, p = 0.04) or CIN+GEN (5.8 vs. 2.8, p = 0.01). Taken as the whole, our data show that CIN+GEN combination is as effective as CIN alone but, regimens containing CIN are more effective to eradicate Y. pestis from the draining lymph node than the recommended GEN monotherapy. Moreover, draining lymph nodes may serve as a reservoir for the continued release of Y. pestis into the blood - even after five days of intravenous antibiotic treatment.

A reliable and safe method of collecting blood samples from implantable central venous catheters for determination of plasma gentamicin concentrations.

STUDY OBJECTIVE: To evaluate the extent of agreement between plasma gentamicin concentrations determined from samples collected by using implantable subcutaneous central venous catheters (ports) with the push-pull method and those collected by finger lancet punctures in children with febrile neutropenia. DESIGN: Prospective, randomized study. SETTING: University-affiliated, tertiary care hospital. PATIENTS: Sixty-two children with cancer who had single- or double-lumen ports and who received gentamicin for treatment of febrile neutropenia between February 2008 and October 2009. INTERVENTION: One blood sample was collected from the port by using the push-pull method at the same time one blood sample was collected by finger lancet puncture for determination of plasma gentamicin concentrations. MEASUREMENTS AND MAIN RESULTS: Forty-four pairs of samples were available for assessment of agreement, and 43 were available for pharmacokinetic analysis. Agreement between plasma gentamicin concentrations determined from blood samples from ports and finger lancet punctures was assessed by the intraclass correlation coefficient (ICC), Bland-Altman analysis, and comparison of simulated dosage adjustments. Changes in port patency were monitored for 1 week after port sampling. Differences in simulated dosage adjustments calculated by using either the port or finger lancet puncture samples that differed by greater than 20% were considered clinically significant. Agreement between the 44 finger lancet puncture and port sample pairs was excellent (ICC 0.991, 95% confidence interval 0.984-0.995). Port plasma gentamicin concentrations were 4.7% lower than those concentrations determined in blood from finger lancet punctures. The observed limits of agreement ranged from -20.5% to 11%. Differences in dosage adjustments calculated by using port and finger lancet puncture plasma gentamicin concentrations were not clinically significant in 38 (88%) of 43 cases. No changes in port patency were observed in the week after port sampling. CONCLUSION: The push-pull method of blood sampling is a reliable and safe option for determining plasma gentamicin concentrations in children with ports.

Once-daily gentamicin dosing in pediatric patients without cystic fibrosis.

STUDY OBJECTIVE: To estimate an appropriate once-daily gentamicin dose and dosing interval for non-critical care pediatric patients older than 3 months of age without cystic fibrosis. DESIGN: Pharmacokinetic analysis of data from a retrospective medical record review. SETTING: Large academic children's hospital. PATIENTS: One hundred fourteen non-critical care pediatric patients older than 3 months of age without cystic fibrosis who received multiple-daily dosing regimens of gentamicin between September 2007 and April 2008. MEASUREMENTS AND MAIN RESULTS: Patient-specific pharmacokinetic parameters were calculated using drug concentrations obtained at steady state. Once-daily doses were extrapolated for each patient to achieve goal peak and trough concentrations. Using the average of these doses and the patient-specific pharmacokinetic parameters, theoretical once-daily peak and trough concentrations were calculated for each patient. Patient characteristics were analyzed to determine differences between patients who did and those who did not achieve adequate peak concentrations. Mean +/- SD pharmacokinetic parameters were as follows: elimination rate constant 0.32 +/- 0.06 hour(-1), half-life 2.28 +/- 0.54 hours, and volume of distribution 0.24 +/- 0.08 L/kg. The only patient demographic characteristic found to have a significant effect on the extrapolated peak concentration was age. The following age-specific once-daily doses were calculated: 3 months to less than 2 years, 9.5 mg/kg; 2 years to less than 8 years, 8.5 mg/kg; and 8-18 years, 7 mg/kg. CONCLUSION: Age was the primary factor in determining the once-daily dose of gentamicin in our pediatric population. Further prospective research is necessary to determine the safety and efficacy of these age-based, once-daily doses for gentamicin.

Once-daily gentamicin dosing in children with febrile neutropenia resulting from antineoplastic therapy.

STUDY OBJECTIVES: To evaluate an existing once-daily gentamicin dosing guideline in children with febrile neutropenia resulting from antineoplastic therapy and, if necessary, to develop a new simulated dosing guideline that would achieve pharmacokinetic targets more reliably after the first dose. DESIGN: Pharmacokinetic analysis of data from a retrospective medical record review. SETTING: Hematology-oncology unit of a university-affiliated pediatric hospital in Canada. PATIENTS: One hundred eleven patients aged 1-18 years who received once-daily gentamicin between April 2006 and January 2008 for the treatment of febrile neutropenia resulting from antineoplastic therapy, and who had plasma gentamicin concentrations determined after their first dose. MEASUREMENTS AND MAIN RESULTS: Demographic data, gentamicin dosing information, blood sampling times, and plasma gentamicin concentrations were noted. Plasma gentamicin concentrations were determined at approximately 3 and 6 hours after the start of the 30-minute infusion of the first dose. Pharmacokinetic parameters were calculated according to standard first-order, one-compartment equations. The proportion of children who achieved pharmacokinetic targets after the first gentamicin dose was used as a measure of dosing guideline performance; the guideline achieved maximum concentration (C(max)) values below the target range (20-25mg/L) in 51% of patients. Ideal dosing guidelines were then developed using the mean dose required to achieved a C(max) of 23 mg/L for each patient. Univariate analysis or the Student t test was used to determine the existence of significant relationships between pharmacokinetic parameters and patient age and sex. The recursive binary partitioning method was used to determine critical values of age for dosage guideline development; analysis of variance was then used to compare the different levels obtained after use of this technique. Simulated administration of once-daily gentamicin in the following doses achieved a C(max) within or above target in 73% of patients: 1 year to < 6 years, 10.5mg/kg/dose; girls > or = 6 years, 9.5mg/kg/dose; and boys > or = 6 years, 7.5mg/kg/dose. Doses were based on actual body weight for children who weighed less than 125% of ideal body weight or based on effective body weight for children 125% or more of ideal body weight. CONCLUSION: The initial gentamicin dosing guidelines were not effective in achieving C(max). The new proposed dosing guidelines are predicted to achieve a C(max) within or above the target range in almost three quarters of patients. Subsequent dosing should be tailored according to plasma gentamicin concentrations.

[Monitoring aminoglycosides in an Intensive Care Unit]. / Monitorage des aminosides en réanimation.

OBJECTIVES: This monocentric, observational and retrospective survey was performed to check the appropriateness between aminoglycoside prescriptions and inhibitor quotient to be reached, in Intensive Care Unit (ICU) patients. We identified variability factors for aminoglycoside plasmatic concentrations at peak such as standardized index of gravity (IGS2 scale), age, sex, weight, and severity of sepsis. PATIENTS AND METHOD: Eighty-seven ICU patients received an antibiotic combination mandatorily including an aminoglycoside (amikacin or gentamicin) as curative treatment for a severe infection. Prescribed dosages were 15mg/kg for amikacin and 5mg/kg for gentamicin. The maximal concentration (Cmax) and minimal inhibiting concentration (MIC) of involved bacteria were recorded. The aminoglycoside ratio Cmax/MIC, called inhibitor quotient, was determined. The inhibitor quotient was considered efficient when superior to 10. The Cmax for aminoglycoside first peak was also compared with the theoretical Cmax to be reached. RESULTS: In the aminoglycoside Cmax, 50.3% were efficient (59.6% for amikacin Cmax and 38.9% for gentamicin Cmax). In 46% of the cases, the inhibitor quotient was efficient; 12.6% of Cmax reached the theoretical Cmax. Factors identified as negatively interacting with biological efficiency were: Gram-positive bacteria or anaerobic bacteria infections and planned surgery. CONCLUSION: In the inhibitor quotients, 49.7% were at inefficient rates, even when the recommended aminoglycoside dosage for was given. Therefore, dose and administration should be updated.

Trafficking of systemic fluorescent gentamicin into the cochlea and hair cells.

Aminoglycosides enter inner ear hair cells across their apical membranes via endocytosis, or through the mechanoelectrical transduction channels in vitro, suggesting that these drugs enter cochlear hair cells from endolymph to exert their cytotoxic effect. We used zebrafish to determine if fluorescently tagged gentamicin (GTTR) also enters hair cells via apically located calcium-sensitive cation channels and the cytotoxicity of GTTR to hair cells. We then examined the serum kinetics of GTTR following systemic injection in mice and which murine cochlear sites preferentially loaded with systemically administered GTTR over time by confocal microscopy. GTTR is taken up by, and is toxic to, wild-type zebrafish neuromast hair cells. Neuromast hair cell uptake of GTTR is attenuated by high concentrations of extracellular calcium or unconjugated gentamicin and is blocked in mariner mutant zebrafish, suggestive of entry via the apical mechanotransduction channel. In murine cochleae, GTTR is preferentially taken up by the stria vascularis compared to the spiral ligament, peaking 3 h after intra-peritoneal injection, following GTTR kinetics in serum. Strial marginal cells display greater intensity of GTTR fluorescence compared to intermediate and basal cells. Immunofluorescent detection of gentamicin in the cochlea also revealed widespread cellular labeling throughout the cochlea, with preferential labeling of marginal cells. Only GTTR fluorescence displayed increasing cytoplasmic intensity with increasing concentration, unlike the cytoplasmic intensity of fluorescence from immunolabeled gentamicin. These data suggest that systemically administered aminoglycosides are trafficked from strial capillaries into marginal cells and clear into endolymph. If so, this will facilitate electrophoretically driven aminoglycoside entry into hair cells from endolymph. Trans-strial trafficking of aminoglycosides from strial capillaries to marginal cells will be dependent on as-yet-unidentified mechanisms that convey these drugs across the intra-strial electrical barrier and into marginal cells.

Evaluation and comparison of simple multiple model, richer data multiple model, and sequential interacting multiple model (IMM) Bayesian analyses of gentamicin and vancomycin data collected from patients undergoing cardiothoracic surgery.

This study compared the abilities of three Bayesian algorithms-simple multiple model (SMM) using a single creatinine measurement; richer data multiple model (RMM) using all creatinine measurements; and the sequential interacting multiple model (IMM)-to describe gentamicin and vancomycin concentration-time data from patients within a cardiothoracic surgery unit who had variable renal function. All algorithms start with multiple sets of discrete parameter support points obtained from nonparametric population modeling. The SMM and RMM Bayesian algorithms then estimate their Bayesian posterior probabilities by conventionally assuming that the estimated parameter distributions are fixed and unchanging throughout the period of data analysis. In contrast, the IMM sequential Bayesian algorithm permits parameter estimates to jump from one population model support point to another, as new data are analyzed, if the probability of a different support point fitting the more recent data is more likely. Several initial IMM jump probability settings were examined-0.0001%, 0.1%, 3%, and 10%-and a probability range of 0.0001% to 50%. The data sets comprised 550 gentamicin concentration measurements from 135 patients and 555 vancomycin concentration measurements from 139 patients. The SMM algorithm performed poorly with both antibiotics. Improved precision was obtained with the RMM algorithm. However, the IMM algorithm fitted the data with the highest precision. A 3% jump probability gave the best estimates. In contrast, the IMM 0.0001% to 50% range setting performed poorly, especially for vancomycin. In summary, the IMM algorithm described and tracked drug concentration data well in these clinically unstable patients. Further investigation of this new approach in routine clinical care and optimal dosage design is warranted.

[Administration and dosing of gentamicin (data from Kaunas University of Medicine Hospital)]. / Gentamicino vartojimo ir dozavimo tyrimas (Kauno medicinos universiteto kliniku duomenys).

UNLABELLED: The aim of the study was to analyze the treatment with gentamicin and possible nephrotoxicity of this antibiotic in patients treated in surgical and internal medicine departments of Kaunas University of Medicine Hospital. MATERIALS AND METHODS: A total of 105 case histories obtained from archive of our hospital were analyzed: 59 case records from surgical and 46 from internal medicine departments. Data were collected regarding indications for the administration of gentamicin, its dosage, duration of treatment, and patients' renal function at the beginning and during the treatment. RESULTS: There were more than 30% of patients older than 65 years. Gentamicin was administered in 14 (23.73%) surgical inpatients to prevent postoperative infection; 45 (76.27%) surgical and 46 (100%) internal medicine inpatients received gentamicin because of symptoms of infection. Half of the patients were treated empirically. In 87.62% of cases, gentamicin was administered at a dose of 240 mg; all 105 patients received it once per day. Before treatment, renal function was not evaluated in 11.86% of surgical and in 19.56% of internal medicine inpatients, and during treatment, it was examined only in one-third of patients. The duration of the treatment was 5.932+/-2.392 days (range 2-13 days) in surgical and 8.283+/-3.344 days (range 3-19 days) in internal medicine inpatients. CONCLUSIONS: More than half of patients received empirical treatment with gentamicin. Not enough attention has been paid to the evaluation of renal function before and during treatment. The duration of treatment was too long.

Systemic absorption of gentamicin nasal irrigations.

OBJECTIVE: To determine if gentamicin nasal irrigation is systemically absorbed, and to identify any ototoxic side effects related to its use. DESIGN: Retrospective review of 12 patients treated with gentamicin nasal irrigations (30 cc of 80 mg/L solution used bilaterally twice daily). METHODS: Serum gentamicin levels were assayed after the course treatment. Pure tone audiometry (250-8000 Hz) and distortion product otoacoustic emissions (DP-OAEs) at 7280, 5133, 3640 and 2560 Hz were obtained before and after therapy. RESULTS: Twelve patients (age 4 to 74, mean 43) with chronic rhinosinusitis were treated for 3-15 weeks (mean 7 weeks). All patients had undergone previous endoscopic sinus surgery. Ten patients had pretreatment cultures that grew organisms sensitive to gentamicin (Pseudomonas, Proteus, or methacillin resistant Staphylococcus aureus), and three patients had cystic fibrosis. Ten of 12 patients (83%) had detectable posttreatment levels of gentamicin, with a mean serum level of 0.42 mcg/mL (range 0.3 to 0.7 mcg/mL). Four of 12 patients (33%) had serum gentamicin levels within the normal range for gentamicin trough (0.5 to 2 mcg/mL). Comparison of pre- and posttreatment audiologic data revealed no significant change in PTA or DP-OAE, except for the right ear at 8000 Hz on PTA (p = 0.035) where a mean of 7 dB loss was observed. No patient reported hearing loss or vertigo during treatment. CONCLUSION: Gentamicin nasal irrigation may be systemically absorbed. Although the otologic consequences of this finding are questionable, patients receiving gentamicin nasal irrigations should be counseled regarding this hypothetical possibility.

Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the disease cystic fibrosis. We previously reported that gentamicin administration suppressed a CFTR premature stop mutation in a Cftr-/- mouse model carrying a human CFTR-G542X (hCFTR-G542X) transgene, resulting in the appearance of hCFTR protein and function. However, the high doses used in that study resulted in peak serum levels well beyond the levels typically administered to humans. To address this problem, we identified doses of both gentamicin and amikacin that resulted in peak serum levels within their accepted clinical ranges. We then asked whether these doses could suppress the hCFTR-G542X mutation in the Cftr-/- hCFTR-G542X mouse model. Our results indicate that low doses of each compound restored some hCFTR protein expression and function, as shown by immunofluorescence and short-circuit current measurements. However, we found that amikacin suppressed the hCFTR-G542X premature stop mutation more effectively than gentamicin when administered at these clinically relevant doses. Because amikacin is also less toxic than gentamicin, it may represent a superior choice for suppression therapy in patients that carry a premature stop mutation in the CFTR gene.