Serum Gentamicin Levels Research Articles

Intra-soft tissue and intramedullary antibiotic perfusion in combination with negative pressure wound therapy.

Intra-soft tissue and intramedullary antibiotic perfusion (iSAP and iMAP), which combine continuous administration of antibiotic solution to the wound and negative pressure wound therapy (NPWT), have been reported to be a useful management approach for hard-to-heal ulcers in the field of orthopaedic surgery. We report the efficacy of this treatment and discuss the key points. The recipients of this treatment had contaminated fresh severe trauma with a high risk of infection, or hard-to-heal ulcers which were expected to be difficult to manage with conventional NPWT alone. Continuous administration of 1200µg/ml of gentamicin (GM) solution to the wound was performed along with NPWT. The GM solution was administered subcutaneously using a small catheter for iSAP, while intramedullary administration used a bone marrow needle for iMAP. iSAP was employed in all 10 patients who took part, and iMAP in three of these patients. The average treatment time was 13.6 days with iSAP and 9.3 days with iMAP. The mean serum GM level during the therapy was 1.02µg/ml. Moderate GM-induced acute kidney injury was suspected in one case, but resolved spontaneously after GM administration was stopped. Favourable wound bed preparation was achieved in all cases without recurrence of infection. Combination with continuous suction by NPWT is able to keep the local concentration of antibiotic above the minimum inhibitory concentration of biofilm-coated bacteria within the wound. We have referred to this treatment as continuous local antibiotic perfusion. Further investigation of local pharmacodynamics in the wound and side-effects of this treatment are warranted.

Assessing the Risk of Nephrotoxicity Associated with Aminoglycosides in Brucellosis Patients: A Cross-sectional Study.

The purpose of this study was to investigate renal function in patients with brucellosis before and at the end of gentamicin therapy. To ensure the safety of therapeutic doses of gentamicin, renal functions in brucellosis patients were monitored regarding drug serum levels and check for early detection biomarkers of nephrotoxicity. In this cross-sectional study, 41 patients (25 men and 16 women, aged over 15 years) were included, with confirmed acute brucellosis that referred to Brucellosis Research Center in Hamadan, west of Iran between March 2018 to February 2019. At baseline before treatment (first step) and 7 days after gentamicin administration (second step), serum uric acid, blood urea nitrogen (BUN), serum and urine creatinine, erythrocyte sedimentation rate (ESR), quantitative C-reactive protein (CRP) and urinary β2-microglobulin (β2M) were measured. Gentamycin serum level due to the highest risk of nephrotoxicity with this drug in aminoglycoside class was also checked by HPLC method. The data were analyzed using SPSS version 22. The mean urinary β 2M level, serum and urinary creatinine, uric acid, BUN, and quantitative CRP levels in the first step and second step, there were no statistical differences between the two steps. There was a correlation between urinary creatinine and ESR. In addition, a positive correlation was found between urinary β2M and serum gentamicin level. ESR levels have been significantly reduced in the patients after the treatment compared to before it. Our findings confirm that gentamicin is safe at the dose of 5 mg/kg/day for one week intravenously in brucellosis patients.

Intravesical gentamicin treatment for recurrent urinary tract infections: A systematic review over the last two decades

Objectives: Recurrent urinary tract infections (rUTIs) have a significant effect on a patient’s quality of life and frequent use of antibiotics increases multi-drug resistance. Previous research on intravesical antibiotics suggests that this has a local effect on bacteria with reduced systemic absorption and associated side effects. We conducted a systematic review to assess the effectiveness and adverse effects of intravesical gentamicin treatment. Methods: Systematic review of all English published articles from January 2001 to October 2021 according to the Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Results: A total of 139 studies were identified, 20 full-text articles were screened and 6 subsequently included totalling 166 patients. All studies reported a decrease in the mean number of urinary tract infections (UTIs) with a significant reduction ( p = 0.0025 and p < 0.004) in two studies. When the number of breakthrough UTIs on prophylactic gentamicin installations was assessed, 65% ( n = 86/133) remained UTI free. Throughout treatment, 99% of serum gentamicin levels were <0.3 ng/dL, and reported instances of increased creatinine were low (2%). A decrease in the growth of multi-drug-resistant bacteria was reported in two papers ( p = 0.065 and p = 0.04). Conclusion: Intravesical gentamicin seems to be an effective treatment in patients with symptomatic rUTIs. The evidence suggests it also reduces UTIs caused by multi-drug-resistant bacteria with no systemic absorption and minimal renal toxicity. Level of evidence: 2a

Intravesical gentamicin instillation in the prevention of recurrent urinary tract infections in children with neurogenic bladder- a single-center retrospective observational study

Recurrent urinary tract infections (UTI) in children with neurogenic bladder (NGB) put them at high risk of morbidity and mortality from urosepsis and end-stage renal disease (ESRD). Since the efficacy of low-dose prophylactic antibiotics to prevent these recurrences has been declining since the emergence of extended-spectrum beta-lactamase (ESBL) organisms, intravesical gentamicin instillation has also been used, but only scarce data in children is available in the literature. We evaluate the efficacy of intravesical gentamicin instillation to reduce UTIs in children with NGB, compare it with oral antibiotic prophylaxis and determine its effect on pathogens resistance to antibiotics. Retrospective observational study of 17 children with NGB managed in a tertiary center. Intravesical gentamicin instillation followed an initial period of oral antibiotic prophylaxis. In a conditional negative binomial regression model, a matched comparison of the rate of UTIs, the identified pathogens and their antibiotics susceptibility between the two therapies was performed for each individual child, RESULTS: When compared to antibiotic prophylaxis, intravesical gentamicin instillation showed no significant difference in the yearly rate of UTI, symptomatic UTI, or admissions for intravenous antibiotic therapy. However, it was associated with a 38% reduction in the incidence rate ratio of UTI (p=0.04) and 75% of asymptomatic UTI (p=0.006) After intravesical gentamicin instillation, five children (31%) had a gentamicin-resistant UTI, similar to before that treatment (p=0.76). Although the overall rate of UTI and of asymptomatic infections were significantly lower with intravesical gentamicin instillation than during oral antibiotic therapy, there was no significant difference in the rate of symptomatic UTIs or UTIs requiring admissions, probably because of the small sample size. In addition, neither an emergence of ESBL pathogens nor the rate of pathogens resistance to gentamicin was observed with intravesical gentamicin instillation. As to the potential nephrotoxicity of aminoglycosides, the calculated GFR for all children remained normal. Strengths of our study include the use of a matched paired comparison of each participant with him/herself with each treatment modality, thus eliminating potential confounding by some individual characteristics. In addition, and unlike previous studies, we have also used a robust multivariate statistical analysis to compare counts and rates of outcomes. Limitations include the absence of gentamicin serum levels monitoring, of hearing testing, and also the small sample size. Intravesical gentamicin instillation decreases the overall rate of UTI and asymptomatic infections in children with NGB without increasing the rate of bacterial resistance to gentamicin.

Intravesical gentamicin instillation for the treatment and prevention of urinary tract infections in complex paediatric urology patients: evidence for safety and efficacy

Little has been reported to date on the instillation of antimicrobials directly into the bladder in children. Children with complex urinary tract anomalies struggle frequently with recurrent urinary tract infections (UTI), with frequent emergence of antibiotic resistance. Gentamicin bladder instillation to treat and prevent UTI was described in children since 2006. We adopted gentamicin bladder instillation in 2016 and evaluate herein our intermediate-term experience with it. This study is a retrospective review of a prospectively initiated database and a clinical audit of our practice. The gentamicin bladder instillation was employed in 24 cases. A treatment regime was initiated for symptomatic documented UTI when resistance patterns precluded an oral alternative (14 cases), avoiding hospitalisation for parenteral antibiotics. A prophylaxis regime (19 cases-including 9 of the 14 who received an initial treatment regime) followed at least one breakthrough UTI while receiving oral prophylactic antibiotics. Two instillation volumes (8mg gentamicin in 20mL 0.9% NaCl or 20mg gentamicin in 50mL 0.9% NaCl) were used to suit different bladder capacities. The irrigation is given twice a day for 7 days in the treatment regime or once a day, every other day, in the prophylactic regime. Gentamicin serum levels (all cases) and audiology/audiometry testing (17/24 cases) were checked to assess the safety of this method. The median age when either the treatment course or prophylaxis regime was started was 3.8 years. The treatment regime was 86% successful (12/14) to suppress an acute UTI. The mean duration of prophylaxis was 252 days (median: 256 days). The percentage of patients on the prophylactic regime who had no breakthrough UTI was 58%. No serum gentamicin was detectable secondary to the intravesical instillation. No attributable cases of sensorineural hearing loss were detected. Gentamicin resistance emerged in one case (4.16%). Intravesical administration was feasible via various routes for a spectrum of complex lower urinary tract abnormalities (see Summary Figure). Concerns regarding systemic absorption, nephrotoxicity or ototoxicity were investigated and safety ensured. Limitations include being a small series of non-identical pathologies, albeit categorically similar and being a single-arm study, however, statistical significance was proven descriptively and analytically. In selected cases and with the appropriate specialist support and logistics, intravesical gentamicin instillation is well-tolerated and safe to treat and/or prevent urinary tract infections in pateints with complex bladder conditions and lower urinary tract pathologies.

Exploring the Relationship between FEV1 Loss and Recovery and Aminoglycoside Pharmacokinetics in Adult Patients with Cystic Fibrosis: Implications for Clinical Dosing Strategies.

Systemic aminoglycosides remain a cornerstone of treatment for cystic fibrosis (CF) pulmonary exacerbations (PEx); however, the impact of aminoglycoside pharmacokinetics (PK) on outcomes is not well defined in adult CF patients. Our objective was to assess the impact of increasing PK exposures on the clinical outcomes of PEx treatment in adult CF patients receiving high-dose and standard-dose extended-interval aminoglycosides. We conducted a retrospective study of adult CF patients treated with an intravenous aminoglycoside for a PEx. Serum amikacin, gentamicin, and tobramycin levels and forced expiratory volume over 1 second (FEV1 ) data were used to evaluate exposure-response relationships. PK parameters were estimated using a Bayesian approach to obtain area under the curve (AUC)0-24 hr , maximum concentration (Cmax0-24 hr ), and minimum concentration (Cmin0-24 hr ) estimates. The primary efficacy end point was a 90% recovery of baseline FEV1 by 30days posttreatment. Toxicity included signs or symptoms of ototoxicity, vestibular toxicity, or renal toxicity. Multivariate linear mixed-effects models of FEV1 were used for exposure-response analysis. The study included 51 patients who contributed 188 FEV1 observations. There were 3.0±1.7 (mean±SD) aminoglycoside concentrations per patient. The mean AUC0-24 hr , Cmax0-24 hr , and Cmin0-24 hr across all agents and patients were 156±96mg*hr/L, 29.9±12.7mg/L, and 0.35±0.66mg/L, respectively. A total of 42 amikacin-, gentamicin-, or tobramycin-treated patients contributed to the efficacy analysis, of whom 85.7% experienced recovery posttreatment. Of the 51 included patients, 6 (11.8%) experienced seven toxicity events. In exploratory exposure-response analyses, neither AUC0-24 hr nor Cmax0-24 hr was associated with FEV1 values after adjusting for clinical covariates and baseline FEV1 . Increasing aminoglycoside AUC0-24 hr and Cmax0-24 hr were not associated with FEV1 during PEx treatment. Although individualizing aminoglycoside dosing in adult CF patients is necessary to minimize toxicity risk, more work is needed to define optimally safe and effective dosing strategies for this population.

Preclinical evaluation of efficacy and pharmacokinetics of gentamicin containing extracellular-matrix envelope.

BackgroundUsing synthetic antibiotic‐eluting envelope (ABE) is an effective intervention for prevention of cardiovascular implantable electronic device (CIED) infection. The biologic extracellular‐matrix envelope (ECME), may offer potential advantages over the synthetic ABE. To further minimize the risk of infection, the ECME can be hydrated in gentamicin prior to CIED implantation. We aimed to evaluate the efficacy and pharmacokinetics (PK) of gentamicin containing ECME in an animal model.MethodsFor all experiments, the ECME was hydrated in gentamicin (40 mg/Ml) (treatment) for 2 min. In vitro antimicrobial efficacy against six different bacterial species was assessed. In vivo experiments were conducted using a rabbit model of CIED pocket infection. Serum and ECM gentamicin concentrations were measured. Five different organisms were inoculated into the device pocket of control (ECME hydrated in 0.9% saline) and treatment groups. Macroscopic appearance and colony forming units from CIED, ECME, and tissue were determined.ResultsNo bacteria were recovered from any culture after 12 h of exposure to the gentamicin containing ECME. Serum gentamicin levels dropped below the limit of quantification at 15 h after implant. Gentamicin concentration in the ECME remained relatively stable for up to 7 days. Signs of clinical infection were observed in the control but not in the treatment group. In the presence of gentamicin, statistically significant reduction was demonstrated across all tested bacterial species.ConclusionsIn this preclinical animal infection model, gentamicin containing ECME was highly effective in reducing bacterial burden in the implant pocket, while systemic exposure after implantation remained low.

The evaluation of the appropriate gentamicin use for preterm infants.

Gentamicin (GM) is used for neonates as the initial treatment for neonatal bacterial infection. An association between high trough GM levels and the elevation of the serum creatinine (sCr) level and hearing loss has been reported, although there have been no reports investigating the serial changes in the sCr level in preterm neonates treated with GM. The present study evaluated the serial changes in the sCr level and the incidence of hearing loss in preterm neonates treated with GM. This study included 56 neonates born at a gestational age of 32-36weeks. Fifteen (group 1) and 20 (group 2) neonates were treated with 2.5mg/kg of GM every 12h and 4mg/kg of GM every 36h, respectively. Group 3 included 21 neonates without GM therapy. Serum GM levels, serial changes in the sCr levels, and the incidence of hearing loss were then compared among the three groups. The serum trough GM level in group 2 was significantly lower than that in group 1 (P < 0.001), whereas the serum peak GM levels in these groups were almost the same. The ratio of the sCr level at birth to that at the 5th day of life in group 1 was the lowest among the 3 groups. No neonates had hearing loss. GM therapy worsened the sCr level in late preterm neonates, especially those with multiple doses per day. The appropriate use of GM is needed in order to prevent the occurrence of nephrotoxicity.

Safety and efficacy of current gentamicin dosing schedules used in neonates in Sri Lanka

Introduction: Gentamicin is the first line antibiotic for early onset neonatal sepsis. Yet the problem with gentamicin is the low therapeutic index. It is known that high trough levels correlate with ototoxicity and nephrotoxicity while the peak levels decide the therapeutic effect. Once daily dose (ODD) and twice daily dose (TDD) schedules are practised in neonatal units in Sri Lanka. Objectives: To assess whether the ODD and TDD schedules of gentamicin used in neonates are effective in avoiding high serum trough levels and in achieving peak serum levels in the therapeutic range. Method: A prospective study was conducted from April to August 2017 in four neonatal units on term neonates less than one week old, in whom gentamicin was started (TDD regime= 2.5 mg/kg 12 hourly and ODD regime= 5mg /kg 24 hourly) during the study period. Trough and peak serum gentamicin levels (SGLs) were assessed before and after the third dose in the TDD regime and after the second dose in the ODD regime. Serum creatinine (SCr) was measured in all the neonates and neonates with high trough levels were referred for hearing assessment. Results: A total of 50 neonates of clinical maturity 37-41 weeks and birth weight 1.8-4.1 kg was included. High trough levels (>2 mg/dl) were seen in 48% of the TDD group and in 12% of the ODD group (p=0.005) Mean trough value in the ODD group was 1.15 mg/dl (SD 0.87) and in the TDD group was 2.14 mg/dl (SD 1.72). (T=-2.564, df=35, p = 0.015). Peak SGL in the therapeutic range (5-10 mg/dl) was seen in 92% of ODD regime and in 80% of the TDD regime. Mean peak values in the ODD and TDD regimes were 9.42 (SD 2.37) mg/dl and 7.12 (SD 2.18) mg/dl respectively (T= 3.56, df=48, p = 0.001). SCr and the hearing assessment were within normal limits in all neonates. Conclusions: The ODD gentamicin schedule of 5 mg/kg achieves a significantly higher peak serum gentamicin level and safer trough levels than the TDD schedule of 2.5 mg/kg.

Individual Control Optimization of Drug Dosage Using Individual Bayesian Pharmacokinetics Model Approach

Giving the right dose of medicine is very important in the healing process from a disease. Improper dosing may worsen the disease or even can cause death. Drug dosing should not only be done based on the population because each individual has different body characteristics. Therefore, the drug dosage was carried out individually using the individual Bayesian pharmacokinetics modeling approach. This case evokes problems regarding how to obtain the estimated population and individual parameters and then determine the optimal dose. The purpose of this analysis is to get the parameters estimation of both population and individual and determine their optimal dose. The data used in this study is patient data who received gentamicin injection. Variables used is gentamicin levels in serum as response variables and sampling times and initial doses as predictor variables. The results obtained are individual pharmacokinetic models with 100% prediction accuracy and dose ranges that can still be tolerated for each individual.

Systemic Absorption of Antibiotics From Antibiotic-Loaded Cement Spacers for the Treatment of Periprosthetic Joint Infection

BackgroundTwo-stage treatment of periprosthetic joint infections involves placement of high-dose antibiotic-loaded cement spacers (ACSs). Reports of ACS-induced nephrotoxicity have raised concern regarding systemic absorption of antibiotics after ACS placement. We sought to characterize the serum concentrations of antibiotics that occur after ACS placement. MethodsWe performed a prospective study of patients with an infected primary total hip (THA) or knee arthroplasty (TKA) treated with standardized ACSs with vancomycin, gentamicin, and tobramycin. Serum antibiotic levels were collected weekly for 8 weeks. ResultsTwenty-one patients (10 THA, 11 TKA) were included. Mean serum gentamicin levels ranged between 0.275±0.046 and 0.364±0.163 mg/L; mean serum tobramycin levels ranged from 0.313±0.207 to 0.527±0.424 mg/L; and mean serum vancomycin levels ranged from 5.46±6.6 to 15.34±9.6 mg/L. Serum antibiotic levels were detectable throughout the 8-week duration of ACS treatment. Regression analysis found that diabetes (coefficient 6.73, 95% CI 0.92-12.54, P < .05), blood urea nitrogen (coefficient 0.83, 95% CI 0.45-1.22, P < .001), number of cement doses (coefficient 3.71, 95% CI 0.76-6.66, P < .05), and use of systemic vancomycin (coefficient 6.24, 95% CI 2.72-9.75, P < .001) correlated with serum vancomycin levels. Patient age (coefficient −0.01, 95% CI −0.02 to 0, P < .01) and male sex (coefficient 0.20, 95% CI 0-0.41, P < .05) correlated with serum aminoglycoside level. ConclusionSystemic absorption of antibiotics from high-dose ACS persists for at least 8 weeks. Patients should be monitored closely for complications related to systemic absorption of antibiotics from ACS treatment.

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

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. 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. 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. This in vivo study suggests safety and efficacy of a novel device for the prevention of intraoperative wound contamination.

The use of intravesical gentamicin to treat recurrent urinary tract infections in lower urinary tract dysfunction

To assess the use of intravesical gentamicin to treat intractable recurrent urinary tract infections in lower urinary tract dysfunction. A two-center retrospective cohort study of 27 patients treated with intravesical gentamicin was performed over a 2-year period. A treatment protocol was developed, reviewed, and accepted by the clinical effectiveness committee of both hospitals. Patients were taught to instill the gentamicin into the bladder on a nightly basis. Inclusion criteria included failure to respond to standard therapy, having six or more cultured confirmed UTIs over a 12-month period, or at least one hospital admission with sepsis. Serum gentamicin levels were taken after 7 days and the treatment was discontinued if the level was >1 mg/L. Patients were counseled about the limited evidence base for this treatment. Twenty-seven patients have been treated with intravesical gentamicin for an average of 26 months. Seventeen were performing ISC, five had suprapubic catheters, three were voiding, and two had ileal conduits at the time of instituting treatment. All patients started on daily 80 mg gentamicin. Twenty two patients had less frequently occurring infections after starting intravesical gentamicin treatment. Six stopped the treatment and none had side effects as a result of the instillations. This study has shown that in a small group of adult patients who have multiple symptomatic UTIs refractory to conventional treatment, intravesical gentamicin is effective in reducing the frequency of infections. The treatment is well tolerated with no evidence of systemic absorption.

Determinants of gentamicin concentrations in critically ill patients: a population pharmacokinetic analysis

When treating critically ill patients with gentamicin for severe infection, peak concentrations (Cmax) determine clinical efficacy and trough concentrations (Cmin) determine toxicity. Despite administration of body weight-standardised starting doses, a wide range of Cmax is generally observed. Furthermore, in therapeutic drug monitoring, several measures of renal function are used to predict appropriate Cmin and gentamicin dosing intervals, but the most accurate predictor is not known. This study aimed to quantify the impact of several patient parameters on gentamicin Cmax values and to determine which measure of renal function best predicts gentamicin clearance (CL). Clinical data and serum gentamicin levels were retrospectively collected from all critically ill patients treated with gentamicin at our intensive care unit between 1 January and 30 June 2011. Data were analysed using non-linear mixed-effects modelling (NONMEM v.7.1.2). A two-compartmental model was developed based on 303 gentamicin concentration–time data from 44 critically ill patients. Serum albumin levels explained 25% of interindividual variability in the volume of distribution (Vd). Creatinine clearance calculated from the creatinine concentration in a 6-h urine portion (CalcCLCr) resulted in acceptable estimation of gentamicin CL, whilst serum creatinine (SCr) and creatinine clearance estimated by the Cockcroft–Gault formula (CGCLCr) overestimated gentamicin CL and therefore underestimated Cmin. In conclusion, low albumin concentrations resulted in a larger Vd and lower Cmax of gentamicin. These results suggest that use of a higher gentamicin starting dose in critically ill patients with hypoalbuminaemia may prevent underdosing. Urinary CalcCLCr is a better predictor of Cmin than SCr or CGCLCr.

Gentamicin Exposure and Sensorineural Hearing Loss in Preterm Infants.

ObjectiveTo evaluate the impact of gentamicin exposure on sensorineural hearing loss (SNHL) in very low birth weight (VLBW) infants.MethodsExposure to gentamicin was determined in infants born between 1993 and 2010 at a gestational age < 32 weeks and/or with a birthweight < 1500 g, who presented with SNHL during the first 5 years of life. For each case, we selected two controls matched for gender, gestational age, birthweight, and year of birth.ResultsWe identified 25 infants affected by SNHL, leading to an incidence of SNHL of 1.58% in our population of VLBW infants. The proportion of infants treated with gentamicin was 76% in the study group and 70% in controls (p = 0.78). The total cumulated dose of gentamicin administered did not differ between the study group (median 10.2 mg/kg, Q1-Q3 1.6–13.2) and the control group (median 7.9 mg/kg, Q1-Q3 0–12.8, p = 0.47). The median duration of gentamicin treatment was 3 days both in the study group and the control group (p = 0.58). Maximum predicted trough serum levels of gentamicin, cumulative area under the curve and gentamicin clearance were not different between cases and controls.ConclusionThe impact of gentamicin on SNHL can be minimized with treatments of short duration, monitoring of blood levels and dose adjustment.

Extended-interval gentamicin administration in neonates: a simplified approach.

Gentamicin dosing is highly variable and remains complicated in the neonatal population. Traditional dosing in our unit resulted in an excessive number of elevated trough serum gentamicin levels. We hypothesized that one uniform gentamicin dose for neonates of all gestational ages will reduce the incidence of elevated trough levels from 50 to 10%. Our prospective, randomized, controlled trial enrolled eligible neonates into two groups, according to gestational age (⩽34 6/7 (group I) and >35 0/7 weeks (group II)). Patients in the study arm received a dose of gentamicin 5 mg kg(-1) intravenous (i.v.) every 36 h, whereas patients in the control arm received traditional dosage. Patients were monitored for resolution of infection, serum gentamicin levels and adverse effects. We confirmed our findings in a follow-up study. Fisher's exact and Mann-Whitney tests were used for statistical analysis. We enrolled 96 neonates, 50 in group I (n=25 per arm) and 46 in group II (n=23 per arm). Elevated trough levels were reduced by 66% in group I (P=0.61) and 100% in group II (P=0.0015). In the study arm of both groups, 48/49 neonates had Cmin serum gentamicin concentration (SGC) <2 mg l(-1) and the majority had a trough SGC <1 mg l(-1) (P<0.0001). The study dose resulted in maximum gentamicin levels in the goal range and a 50% reduction in dosage modifications. There were no treatment failures or adverse effects. Our follow-up study phase confirmed these results. A standardized gentamicin dosage of 5 mg kg(-1) i.v. every 36 h to neonates of all gestational ages was safe and resulted in SGCs in goal therapeutic ranges. The implications of this simplified gentamicin dosage are to reduce health-care costs by less frequent dosing of gentamicin and reducing medication errors in physician prescribing from complicated dosing schemes.

84: Extended Interval Gentamicin Dosing in Preterm Neonates Less Than 35 Weeks Corrected Gestational Age

Extended interval gentamicin dosing in neonates <35 weeks corrected gestational age (CGA) has been shown to achieve optimal serum peak concentrations compared to traditional once daily doses. However recommendations on exact dose and frequency vary. After a literature review, a dose of 5 mg/kg/dose every 48 hours was implemented at our institutions. To characterize concentration-time profiles achieved with a gentamicin dose of 5 mg/kg every 48 hours in neonates <35 weeks CGA. To identify gentamicin pharmacokinetic parameters in neonates <35 weeks CGA: half-life (t1/2), clearance, and volume of distribution (V1). Pharmacokinetics were prospectively analyzed after implementation of 5 mg/kg gentamicin as a single empiric dose for sepsis in neonates <35 weeks CGA (n=54). Serum samples were drawn at approximately 1 h, 24 h, and 48 h post dose. Target serum concentrations were 6–12 mg/L and 0.5–2 mg/L at 1 h and 48 h, respectively. Pharmacokinetic analysis was performed on available samples to determine if birth weight, gender, gestational age at birth, CGA, or postnatal age (PNA) affect gentamicin clearance, t1/2, V1, or serum levels. A one-compartment model best represented the pharmacokinetics of gentamicin for our population. Average pharmacokinetic parameters were: clearance 42±10 mL/kg/h, V1 0.578±0.087 L/kg, and t1/2 9.98±1.84 h. In all treatment courses when at least two serum levels were drawn (n=44), mean levels extrapolated to 1 h, 24 h, and 48 h were 8.24±1 mg/L, 1.6±0.48 mg/L, and 0.31±0.16 mg/L respectively. Neonates <14 days PNA had significantly higher gentamicin levels at 24 h (1.7±0.3 mg/L vs. 1.1±0.7 mg/L, P=0.002) and at 48 h post dose (0.34±0.14 mg/L vs. 0.2±0.2 mg/L, P=0.03). Clearance was significantly lower in neonates <14 days PNA (mean 38±5 mL/kg/h vs. 55±18 mL/kg/h, P=0.01) but was not affected by other covariates. V1 was not influenced by any covariates. A gentamicin dose of 5 mg/kg in neonates <35 weeks CGA and <14 days PNA results in post serum levels of 6–12 mg/L. Gentamicin clearance in neonates <35 weeks CGA was not affected by gestational age at birth, CGA, gender, or birth weight but increased as PNA increased suggesting the need to dose gentamicin more frequently than every 48 hours in neonates 14 days PNA. The risk of medication error may be reduced from this simplified approach.

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

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. 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 24h after implantation of gentamicin-impregnated multifilament meshes in 19 patients. 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 6h after implantation of the gentamicin-impregnated meshes were below the through-level (range 0.4-2.9mg/l, mean 1.2±0.7mg/l). After 24h the gentamicin serum levels in all patients had declined 90-65% of the 6h values. 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.

ABSTRACT 723

Background and aims: Once daily dosing (ODD) of aminoglycosides has been shown to be less toxic and as efficacious as multiple daily dosing regimens. There is a lack of pharmacokinetic (PK), safety, and efficacy data for aminoglycoside ODD in critically ill paediatric patients. Aims: To evaluate the proposed exclusion criteria for use of ODD gentamicin by examining gentamicin PK disposition in patients excluded from ODD therapy, and to adapt the criteria as appropriate. Methods: A retrospective chart review (approved by Research and Ethics Board) of 176 critically ill paediatric patients excluded from ODD therapy was done. PK parameters were calculated based on available therapeutic drug monitoring (TDM) levels. Extrapolated serum gentamicin levels achieved using a dose of 9 mg/kg were calculated and used to determine whether an excluded patient would have adequately cleared ODD gentamicin. Exploratory analyses were done to assess other characteristics that may predict if a patient will adequately clear ODD gentamicin despite prior exclusion. Results: The majority of patients (56%) were excluded from ODD therapy based on having a weight of ≤5 kg. Thirty-nine percent of patients excluded due to weight may have been able to adequately clear ODD gentamicin based on extrapolated PK parameters. Of these patients, 53% were estimated to achieve target Cmax, and 97% were estimated to achieve target drug-free interval. Conclusions: Patients with a weight of ≤5 kg can potentially be considered a conditional exclusion criterion, whereupon critically ill pediatric patients started on gentamicin for non-cardiac indications can be subsequently switched to gentamicin ODD if TDM levels show adequate clearance.

The Role of Monitoring Gentamicin Levels in Patients with Gram-Negative Peritoneal Dialysis-Associated Peritonitis

There is limited available evidence regarding the role of monitoring serum gentamicin concentrations in peritoneal dialysis (PD) patients receiving this antimicrobial agent in gram-negative PD-associated peritonitis. Using data collected in all patients receiving PD at a single center who experienced a gram-negative peritonitis episode between 1 January 2005 and 31 December 2011, we investigated the relationship between measured serum gentamicin levels on day 2 following initial empiric antibiotic therapy and subsequent clinical outcomes of confirmed gram-negative peritonitis. Serum gentamicin levels were performed on day 2 in 51 (77%) of 66 first gram-negative peritonitis episodes. Average serum gentamicin levels on day 2 were 1.83 ± 0.84 mg/L with levels exceeding 2 mg/L in 22 (43%) cases. The overall cure rate was 64%. No cases of ototoxicity were observed. Day-2 gentamicin levels were not significantly different between patients who did and did not have a complication or cure. Using multivariable logistic regression analysis, failure to cure peritonitis was not associated with either day-2 gentamicin level (adjusted odds ratio (OR) 0.96, 95% confidence interval (CI) 0.25 - 3.73) or continuation of gentamicin therapy beyond day 2 (OR 0.28, 0.02 - 3.56). The only exception was polymicrobial peritonitis, where day-2 gentamicin levels were significantly higher in episodes that were cured (2.06 ± 0.41 vs 1.29 ± 0.71, p = 0.01). In 17 (26%) patients receiving extended gentamicin therapy, day-5 gentamicin levels were not significantly related to peritonitis cure. Day-2 gentamicin levels did not predict gentamicin-related harm or efficacy during short-course gentamicin therapy for gram-negative PD-related peritonitis, except in cases of polymicrobial peritonitis, where higher levels were associated with cure.