Therapeutic Drug Monitoring Of Gentamicin Research Articles

Impact of the PK/PD Approach in Therapeutic Drug Monitoring of Gentamicin

Gentamicin, a commonly used hospital aminoglycoside, exhibits a narrow therapeutic index, necessitating careful administration to prevent serious adverse effects. Our study aimed to assess the impact of Therapeutic drug Monitoring (TDM) by integrating Minimum Inhibitory Concentration (MIC) to customize dosage based on bacterial sensitivity. This was prospective study, conducted on a sample of 35 adult patients hospitalized in three university hospital centers in Eastern Algeria. Included patients underwent Therapeutic Drug Monitoring (TDM) of gentamicin based on the determination of Maximum concentration (Cmax), considering the determination of the MIC and achieving a Cmax/CMI ratio ≥ 8 to 10. Pharmaceutical interventions were suggested to clinicians to improve patient care. The mean age of our patients was 51.66 ± 16.72 years. All patients had Cmax values below the therapeutic range. Pathogenic microorganisms were identified in 64% of cases, and only two patients achieved the Cmax/CMI target of 8 to 10 prior to our interventions. In 41% of cases, clinicians heeded our guidance on regular therapeutic monitoring and dose adjustments. The therapeutic target was achieved in 66.6% of cases, with a Cmax/CMI target attainment rate of 44.4%.The use of individualized initial doses of gentamicin, combined with Therapeutic Drug Monitoring based on PK/PD parameters, enhances the chances of therapeutic success and restricts the emergence of bacterial resistance.

Saliva as a sampling matrix for therapeutic drug monitoring of gentamicin in neonates: A prospective population pharmacokinetic and simulation study.

AimsTherapeutic drug monitoring (TDM) of gentamicin in neonates is recommended for safe and effective dosing and is currently performed by plasma sampling, which is an invasive and painful procedure. In this study, feasibility of a non‐invasive gentamicin TDM strategy using saliva was investigated.MethodsThis was a multicentre, prospective, observational cohort study including 54 neonates. Any neonate treated with intravenous gentamicin was eligible for the study. Up to eight saliva samples were collected per patient at different time‐points. Gentamicin levels in saliva were determined with liquid chromatography tandem mass‐spectrometry (LC–MS/MS). A population pharmacokinetic (PK) model was developed using nonlinear mixed‐effects modelling (NONMEM) to describe the relation between gentamicin concentrations in saliva and plasma. Monte Carlo simulations with a representative virtual cohort (n = 3000) were performed to evaluate the probability of target attainment with saliva versus plasma TDM.ResultsPlasma PK was adequately described with an earlier published model. An additional saliva compartment describing the salivary gentamicin concentrations was appended to the model with first‐order input (k13 0.023 h−1) and first‐order elimination (k30 0.169 h−1). Inter‐individual variability of k30 was 38%. Postmenstrual age (PMA) correlated negatively with both k13 and k30. Simulations demonstrated that TDM with four saliva samples was accurate in 81% of the simulated cases versus 94% when performed with two plasma samples and 87% when performed with one plasma sample.ConclusionTDM of gentamicin using saliva is feasible and the difference in precision between saliva and plasma TDM may not be clinically relevant, especially for premature neonates.

A Retrospective Review of the Efficiency of First-Dose Therapeutic Drug Monitoring of Gentamicin, Amikacin, and Vancomycin in the Pediatric Population.

Therapeutic drug monitoring (TDM) has become standard clinical practice for gentamicin, amikacin, and vancomycin to optimize efficacy and reduce toxicity. TDM after the first dose of antibiotic was adopted in our institution. This study aims to evaluate if target therapeutic drug concentrations could be achieved more rapidly in patients with TDM performed after the first dose of gentamicin, amikacin, or vancomycin compared to TDM at steady state. A single-center retrospective cohort study was conducted at KK Women's and Children's Hospital, Singapore. Patients aged 1 month to 18 years old who received amikacin, gentamicin, or vancomycin between October 2012 to March 2016 and had at least 2 serum drug concentrations done within the same dosing interval were included. The primary objective was to compare the time taken to achieve target serum drug concentrations between first-dose and steady-state TDM. A total of 334 patients on amikacin, 211 patients on gentamicin, and 140 patients on vancomycin were included. Using Kaplan-Meier analysis, the median number of days to optimize therapy was significantly shorter after first-dose TDM was performed for amikacin (first dose, 1.51 [95% confidence interval (CI), 1.44-1.89] days vs steady state, 2.85 [95%CI, 2.50-3.25] days; P < .01] and gentamicin (first dose, 1.66 [95%CI, 1.25-2.08] days vs steady state, 3.54 [95%CI, 2.40-4.75] days; P < .01] but not vancomycin (first dose, 1.34 [95%CI, 1.06-1.52] days vs steady state, 1.42 [95%CI, 1.26-1.59] days; P = .99]. First-dose TDM for gentamicin and amikacin resulted in faster attainment of target serum concentrations but did not for vancomycin. Further validation of its impact on actual clinical outcomes may be required.

In vitro evaluation of an intravenous microdialysis catheter for therapeutic drug monitoring of gentamicin and vancomycin.

A central venous catheter with a built‐in microdialysis membrane is available for continuous lactate and glucose monitoring in the intensive care unit (ICU). As this catheter might also be suitable for repeated measurements of unbound drug levels, we studied in vitro the feasibility of monitoring unbound antibiotic concentrations. The catheter was placed in various media at 37°C spiked with gentamicin or vancomycin. Dialysate fractions were repeatedly collected over 3 hours with a NaCl 0.9% perfusate flow of 5 μL/min. Total and unbound drug concentrations in medium and perfusate were measured by immunoassay. After 60 minutes stable recovery for both drugs was observed, with mean ±SD relative recoveries of vancomycin and gentamicin in human serum of 64% ±0.4% and 73% ±3%. The recoveries of the unbound concentrations were 91% ±3% and 91% ±4%. This intravenous microdialysis system may be a very useful platform for therapeutic drug monitoring in the ICU.

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Impact of Clinical Decision Support Guidelines on Therapeutic Drug Monitoring of Gentamicin in Newborns

Our institution's gentamicin dosing and therapeutic drug monitoring (TDM) practices for newborns were suspected to be very heterogeneous. Once-daily dosing (ODD) or extended-interval dosing (EID) and trough concentration measurement were recommended. Clinical decision support guidelines were developed and implemented as clinical decision support in the computerized prescriber order entry system. Impact on dosing, TDM practices, and blood sampling were evaluated. A 1-year retrospective historically controlled study before (April 2008-March 2009) and after the implementation of guidelines (January 2010-December 2010) for newborns (<30 days of life) receiving gentamicin. Blood concentrations (% of peak concentrations sampled, % of patients with zero or one concentration sampled, % of trough concentrations ≤1 mg/L) and dose regimen (ODD/EID) were compared between groups. Factors potentially associated with gentamicin concentration were analyzed (multivariate analysis). One hundred thirty-two (postguidelines) versus 102 (preguidelines) patients were included (median gestational age: 34.3 versus 35.8 weeks, P > 0.05). After implementation of the guidelines, an ODD/EID regimen was almost exclusively used (97.7% versus 61.6%, P < 0.001), the percentage of peak concentrations (0.9% versus 17.2%, P < 0.001) and the number of blood samples per patient (87.1% having 0 or 1 concentration measured versus 48.0, P < 0.001) sharply reduced. A significantly higher percentage of trough concentrations were ≤1 mg/L (68.5% versus 33.0%, P < 0.001). The probability of a trough concentration ≤1 mg/L increased with an ODD/EID regimen (odds ratio, 7.23; 95% confidence interval: 3.48-15.0, P < 0.001) and in the postguidelines group (odds ratio, 2.02; 95% confidence interval: 1.01-4.02, P = 0.045). Guideline implementation generated a sharp reduction in blood sampling. Clinical benefits of better gentamicin dosing and TDM practices were evident. Cost-effectiveness and clinical benefit of reduced blood sampling should be evaluated.

Barriers to the safe and effective use of intravenous gentamicin and vancomycin in Scottish hospitals, and strategies for quality improvement

ObjectivesAvoiding harm when patients interact with healthcare services is a global issue. Guidelines are often produced to improve the prescribing and monitoring of medication with a narrow therapeutic index. Adherence...

Cost evaluation of therapeutic drug monitoring of gentamicin at a teaching hospital in Malaysia

Therapeutic drug monitoring (TDM) makes use of serum drug concentrations as an adjunct to decision-making. Preliminary data in our hospital showed that approximately one-fifth of all drugs monitored by TDM service were gentamicin. In this study, we evaluated the costs associated with providing the service in patients with bronchopneumonia and treated with gentamicin. We retrospectively collected data from medical records of patients admitted to the Hospital Universiti Sains Malaysia over a 5-year period. These patients were diagnosed with bronchopneumonia and were on gentamicin as part of their treatment. Five hospitalisation costs were calculated; (i) cost of laboratory and clinical investigations, (ii) cost associated with each gentamicin dose, (iii) fixed and operating costs of TDM service, (iv) cost of providing medical care, and (v) cost of hospital stay during gentamicin treatment. There were 1920 patients admitted with bronchopneumonia of which 67 (3.5%) had TDM service for gentamicin. Seventy-three percent (49/67) patients were eligible for final analysis. The duration of gentamicin therapy ranged from 3 to 15 days. The cost of providing one gentamicin assay was MYR25, and the average cost of TDM service for each patient was MYR104. The average total hospitalisation cost during gentamicin treatment for each patient was MYR442 (1EUR approx. MYR4.02). Based on the hospital perspective, in patients with bronchopneumonia and treated with gentamicin, the provision of TDM service contributes to less than 25% of the total cost of hospitalization.

Effects of clinical decision support on the TDM of gentamicin and vancomycin in newborns

BackgroundThe dosing scheme for gentamicin and therapeutic drug monitoring (TDM) of gentamicin and vancomycin in newborns were evaluated as very heterogeneous in our institution. Once daily dosing (ODD) of gentamicin...

Therapeutic drug monitoring of gentamicin in patients with bronchopneumonia: cost considerations and patient outcomes.

In Malaysia, therapeutic drug monitoring (TDM) service started in the late 1980s. Serum concentration measurements depend on commercially available drug assays, which are costly. In the present study, we attempted to document the impact of TDM service on cost and patient outcomes. We reviewed the medical records of the patients who were admitted to the hospital over a five-year period, diagnosed with bronchopneumonia and treated with gentamicin. Outcome measures were duration of fever, incidence of nephrotoxicity and length of hospital stay. We calculated the costs of laboratory and clinical investigations, the costs associated with the administration of gentamicin doses, the cost of providing TDM services, the costs associated with medical care by professional staff and the costs of hospital stays during gentamicin treatment. Sixty-six patients were found to meet the inclusion criteria (10 patients were provided with TDM service and 56 patients were not). There was no significant difference in the duration of fever or the length of hospital stay during gentamicin therapy between the two groups. Although serum creatinine levels were not checked in all of the patients after gentamicin therapy, the data analysis did not show any cases of nephrotoxicity. There was no significant difference in the costs of laboratory investigations, the total cost of gentamicin therapy and the costs associated with professional staff between the two groups. The cost of the hospital stay during gentamicin therapy and the total cost of hospitalization were significantly higher in the TDM group. Evaluation in patients with bronchopneumonia shows that TDM in our setting was associated with higher cost; however, we did not observe any significant differences in the clinical outcomes.

Therapeutic Drug Monitoring of Gentamicin in Neonatal Intensive Care Unit: Experience in 68 Newborns

SummaryA proper dosing regimen is fundamental when antibiotics with a low therapeutic index, as aminoglycosides (AMG), are used. AMG pharmacokinetics present a strong interindividual and intraindividual variability in neonates; in the premature neonate AMG clearance is reduced and the half-life is longer, leading to higher serum trough concentrations. Neonates may require therapeutic drug monitoring (TDM) and a “tailored” therapeutic regimen. The aim of this work is to present our personal experience with TDM of gentamicin in 68 newborns and to compare it with data available in the literature.

Therapeutic Drug Monitoring of Gentamicin: Evaluation of Five Nomograms for Initial Dosing at Al-Amiri Hospital in Kuwait

Objective: To compare five published nomograms (Thomson guidelines, Mawer nomogram, rule of eights, Hull-Sarubbi table and Dettli method) for calculating the initial gentamicin dosage regimen in a Kuwaiti population. Materials and Methods: Based on measured peak and trough gentamicin concentrations, the elimination rate constant and volume of distribution of gentamicin were calculated for each patient (n = 56), using a modified two-point Sawchuk-Zaske method. The calculated individual set of pharmacokinetic parameters and the initial dose regimen recommended by each of the five methods were used to predict the steady-state peak and trough of gentamicin concentrations. Results: The Thomson guidelines produced consistent results in predicting gentamicin concentrations within the target ranges of peak plus trough, peak only and trough only (63, 75 and 75%, respectively). The Mawer nomogram, Hull-Sarubbi table and Dettli methods achieved similar percentages of patients (46–50%) within the target ranges (5–10 mg · l^–1 for peak and 0.5–2 for trough), whereas empirical dosing and the rule of eights showed the lowest percentages of patients within the peak plus trough target range (25 and 37%, respectively). However, with respect to the underdosing target range (predicted concentration <5 mg · l^–1), the Thomson guidelines showed that 21% of patients were underdosed. Conclusion: The results show that a large number of patients (37–63%) were outside the target ranges in all initial gentamicin dosing methods evaluated in this study. Therefore, serum concentration measurement can be advised to assist in the optimization of gentamicin dose selection.

筋ジストロフィー患者に対するゲンタマイシン療法時における腎機能評価

Recently, high dose gentamicin (GM) has started to be used for the treatment of Duchenne muscular dystrophy (DMD). Previously, since the intravenous infusion of GM for 1h once a week at a dose of 7.5 mg/kg/day had caused no significant adverse events in a course of therapy lasting 6 months, we decided to try conducting such therapy for four courses in the present study. We continuously assessed renal function by monitoring serum creatinine, serum cystatin C (Cys-C), serum urea nitrogen (BUN), urinary β2-microglobulin and urinary N-acetyl-β-D-glucosaminidase (NAG) activity. Serum creatinine levels were found to be much lower than the normal range, while, at 0.65 to 0.78μg/mL, serum Cys-C levels, were within the normal range and so was BUN, suggesting that the glomerular filtration rate in the DMD patients receiving GM therapy was being maintained in the normal range. Therapeutic drug monitoring of GM indicated that it was being rapidly eliminated from the systemic circulation though a slight elevation of urinary NAG activity in 1 patient indicated the possibility of impaired renal proximal tubules. It will thus be necessary to optimize our patient management strategy.

Pharmacokinetics and therapeutic drug monitoring of gentamicin in the elderly.

Gentamicin is frequently used in elderly patients as serious infection, particularly Gram-negative bacilli, remains one of the major health problems experienced by this age group. A number of physiological changes in drug disposition occur with ageing and potentially these can affect gentamicin pharmacokinetics. In particular, there is a measurable decline in renal function, especially after the aged of 65. Any differences in drug distribution with age are apparently not reflected in gentamicin disposition data, as patients of varying ages have similar volumes of distribution. Seriously ill patients with infections frequently require treatment with many different drugs. Of note, the combination of gentamicin and a beta-lactam antibacterial can result in inactivation. However, there appears to be no published data describing detrimental or beneficial pharmacokinetic interactions between gentamicin and drugs used in the elderly. Nonetheless, gentamicin should be used cautiously in order to prevent potential exacerbation of its nephrotoxicity and/or ototoxicity. Such problems may occur as a result of coadministration with, for example, amphotericin, cisplatin, vancomycin, foscarnet, nonsteroidal anti-inflammatory drugs or furosemide (frusemide). The presence of concurrent disease in aged patients (e.g. malignancy, fluid balance disorders and sepsis) may cause problems. In sepsis, for example, the volume of distribution of gentamicin may be increased; however, other pharmacokinetic data are contradictory and inconclusive. Like other aminoglycosides, gentamicin has a narrow therapeutic index and therapeutic drug monitoring has proven to be beneficial, particularly in vulnerable populations such as the elderly. Moreover, there is substantial pharmacokinetic variability in these patients. Recent data support the use of extended interval or once daily doses of gentamicin. It has been suggested that because of a lack of studies for this regimen in the elderly, specific recommendations cannot yet be made. We would argue that some recommendations for its cautious adoption in aged patients could be justified. Suggested procedures for the once daily administration of gentamicin include the use of the 'Hartford' nomogram and the targeted area under the concentration-time curve. The susceptibility of the elderly to aminoglycoside-related nephrotoxicity (and probably ototoxicity) may arise from a decline in renal function and an impaired capacity for cellular repair and regeneration. However, of greater importance is the duration of aminoglycoside therapy and the concomitant use of other nephrotoxic drugs. Further confirmation of the utility and tolerability of the once daily regimen and other possible approaches to gentamicin therapy in the elderly are essential.

Therapeutic drug monitoring of gentamicin: a 6-year follow-up audit.

In 1984 a therapeutic drug monitoring (TDM) service was established in Hospital Universiti Sains Malaysia (HUSM) and gentamicin concentrations were measured and used to design optimal regimens for the antibiotic. In this study we report on a 6-year follow-up audit since our first assessment of the service. Records of 733 requests for gentamicin monitoring were reviewed. Of the 592 patients involved, 39% were neonates and 42% were adults. Peak gentamicin concentrations were within the therapeutic range in 65% of the patients at first monitoring and 79% of the corresponding trough concentrations were within the non-toxic range. After dosage adjustment, 81% of the peak concentrations were within the therapeutic range and trough concentrations rose to levels regarded as toxic in 7% of patients. In patients with therapeutic peak concentrations at the first monitoring point, the average duration of gentamicin therapy was statistically shorter than in those patients who failed to achieve a therapeutic peak concentration. The distribution of gentamicin peak and trough concentrations in terms of therapeutic ranges were also better than those found in 1990. TDM for gentamicin is well accepted in HUSM and its application has contributed to improved gentamicin administration. Furthermore, our physicians are now able to choose more appropriate dosage regimens for their patients because the majority of gentamicin concentrations attained even at the first monitoring were within the therapeutic range.