Dose Of Gentamicin Research Articles

Hemopexin, a potential biomarker for the diagnosis of chronic predisposition to acute kidney injury

In the last years, the new concept of predisposition to acquire acute kidney injury (AKI) is emerging. This concept was observed in our group when experimental animals exposed to an absolutely subnephrotoxic acute treatment with certain drugs (e.g. gentamicin and cisplatin) developed AKI when they were treated with a second insult with another drug, while control animals exposed to the same second drug experimented no toxicity. On these grounds, we decide to study if chronic exposure to nephrotoxicants might induce this predisposition to AKI and investigate how to detect this condition by the search of predisposition biomarkers. To this end, rats (Sprague-Dawley) were treated with a subtoxic dosage of the experimental nephrotoxin uranyl nitrate (UN) in the drinking water for 22 weeks, or plain water (as control). After 21 weeks both groups were treated with subtoxic regime of getamicin during 7 days. Renal function was monitored by means of serum creatinine, serum urea, proteinuria, N-acetyl-beta-D-glucosaminidase and lactate dehydrogenase excretion measurement. After and before gentamicin treatment a subset of rats were sacrificed and their kidneys used for histology. With the purpose of identifying biomarker of predisposition, proteomic studies were performed before gentamicin administration at week 21. Chronic administration of UN in drinking water during 21 weeks did not modify renal function or renal tissue integrity. However, when rats exposed to UN during 21 weeks where challenged with low doses of gentamicin, they developed an overt renal failure as shown by an increase in creatinine, urea and by histological alterations. These alterations were not observed in the control group. Using a proteomic analysis, hemopexin was detected which was validated by Western blot. Urinary excretion of hemopexin was statically higher in the exposed group than in the control group. Our results suggest that chronic exposure to UN, at doses that apparently does not produce damage, predisposes to AKI when animals were subjected to a second insult at subtoxic doses. Hemopexin protein might be potentially used as marker of chronic predisposition to ARF. This new diagnostic tool might help to reduce AKI incidence and severity, and also the associated sanitary and socioeconomic costs.

Development of an “In Situ” renal perfusion system to study the origin of urinary biomarkers in a nephrotoxicity model induced by gentamicin

Background and AimsGentamicin is an aminoglycoside antibiotic widely used for the treatment of many infectious diseases. Its main side effect is its nephrotoxicity, which occurs in 10-25% of therapeutic courses, despite proper monitoring and hydration of patients, can lead to acute kidney injury (AKI). We have previously demonstrated that urinary damage markers like albuminuria increased as a consequence of the addition of gentamicin. In the present work we aimed at specifically studying the renal handling of albuminuria in a nephrotoxicity model, through in situ renal perfusion experiments. MethodsMale Wistar rats were administrated by a single dose of gentamicin (150mg/kg), or not. After 5 days, rats were anesthetized and an extracorporeal circuit for kidney perfusion was set up. The renal artery, vein and ureter of the right kidney were ligated. The renal artery of the left kidney and the urinary bladder were canulated. A catheter was placed in the right carotid artery and connected directly to the renal artery. Urine was continuously collected from a catheter placed in the urinary bladder at 10min intervals. After 1h of renal perfusion with blood from the carotid artery, oxygenated and warm (37 °C) Krebs-dextran (40g/L of dextran) was perfused through the renal artery at 3mL/min, and was discarded through the renal vein. Albuminuria was measured in the different urine fractions. ResultsFrom the second day after gentamicin administration, albuminuria was significantly increased, as compared to control rats, in which urinary markers were undetectable. When exogenous Krebs solution prefunding the kidney, neither gentamicin rats nor control rats excreted albuminuria. As a control of the perfusion experiments, urinary markers still appeared in the urine in gentamicin rats whose kidney was perfused with its own blood. However, albuminuria was undetectable in control rats. ConclusionsOur results support the idea that excess albumin found in the urine (albuminuria) as a consequence of treatment with gentamicin comes from the blood ultrafiltrate reaching Bowman’s capsule and not from the renal parenchyma. More interestingly, our results provide and in situ method to test the origin of urinary biomarkers in different conditions.

Stochastic process pharmacodynamics: dose timing in neonatal gentamicin therapy as an example.

We consider dosing regimens designed to cure patients by eradicating colony forming units (CFU) such as bacteria. In the field of "population" pharmaco-kinetics/dynamics (PK/PD), inter-individual variability (IIV) of patients is estimated using model parameter statistical distributions. We consider a more probabilistic approach to IIV called stochastic process theory, motivated by the fact that tumor treatment planning uses both approaches. Stochastic process PD can supply additional insights and suggest different dosing regimens due to its emphasis on the probability of complete CFU eradication and its predictions on "pure chance" fluctuations of CFU number per patient when treatment has reduced this integer to less than ~100. To exemplify the contrast between stochastic process PD models and standard deterministic PD models, which track only average CFU number, we analyze, neglecting immune responses, neonatal intravenous gentamicin dosing regimens directed against Escherichia coli. Our stochastic calculations predict that the first dose is crucial for CFU eradication. For example, a single 6mg/kg dose is predicted to have a higher eradication probability than four daily 4mg/kg doses. We conclude: (1) neonatal gentamicin dosing regimens with larger first doses but smaller total doses deserve investigation; (2) in general, if standard PK/PD models predict average CFU number drops substantially below 100, the models should be modified to incorporate stochastic effects more accurately, and will then usually make more favorable, or less unfavorable, predictions for front boosting ("hit hard early"). Various caveats against over-interpreting the calculations are given.

Antibiotic regimens for postpartum endometritis.

Postpartum endometritis occurs when vaginal organisms invade the endometrial cavity during the labor process and cause infection. This is more common following cesarean birth. The condition warrants antibiotic treatment. Systematically, to review treatment failure and other complications of different antibiotic regimens for postpartum endometritis. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2014) and reference lists of retrieved studies. We included randomized trials of different antibiotic regimens after cesarean birth or vaginal birth; no quasi-randomized trials were included. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The review includes a total of 42 trials, and 40 of these trials contributed data on 4240 participants.Regarding the primary outcomes, seven studies compared clindamycin plus an aminoglycoside versus penicillins and showed fewer treatment failures (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.46 to 0.90). There were more treatment failures in those treated with an aminoglycoside plus penicillin when compared to those treated with gentamycin/clindamycin (RR 2.57, 95% CI 1.48 to 4.46). There were more treatment failures (RR 1.66, 95% CI 1.01 to 2.74) and wound infections (RR 1.88, 95% CI 1.08 to 3.28) in those treated with second or third generation cephalosporins (excluding cephamycins) versus those treated with clindamycin plus gentamycin. In four studies comparing once-daily with thrice-daily dosing of gentamicin, there were fewer failures with once-daily dosing. There were more treatment failures (RR 1.94, 95% CI 1.38 to 2.72) and wound infections (RR 1.88, 95% CI 1.17 to 3.02) in those treated with a regimen with poor activity against penicillin-resistant anaerobic bacteria as compared to those treated with a regimen with good activity against penicillin-resistant anaerobic bacteria. There were no differences between groups with respect to severe complications and no trials reported any maternal deaths.Regarding the secondary outcomes, three studies that compared continued oral antibiotic therapy after intravenous therapy with no oral therapy, found no differences in recurrent endometritis or other outcomes. Four trials that compared clindamycin plus aminoglycoside versus cephalosporins identified fewer wound infections in those treated with clindamycin plus an aminoglycoside (RR 0.53, 95% CI 0.30 to 0.93). There were no differences between groups for the outcomes of allergic reactions. The overall risk of bias was unclear in the most of the studies. The quality of the evidence using GRADE comparing clindamycin and an aminoglycoside with another regimen (compared with cephalosporins or penicillins) was low to very low for therapeutic failure, severe complications, wound infection and allergic reaction. The combination of clindamycin and gentamicin is appropriate for the treatment of endometritis. Regimens with good activity against penicillin-resistant anaerobic bacteria are better than those with poor activity against penicillin-resistant anaerobic bacteria. There is no evidence that any one regimen is associated with fewer side-effects. Following clinical improvement of uncomplicated endometritis which has been treated with intravenous therapy, the use of additional oral therapy has not been proven to be beneficial.

Gentamicin and renal function: lessons from 15 years' experience of a pharmacokinetic service for extended interval dosing of gentamicin.

Extended interval dosing (EID) of gentamicin most commonly involves dosing every 24 hours, but patients with impaired renal function may require a longer dose interval. This study examines a large database of patients treated with gentamicin from 1996 to 2010 to see how many patients with renal impairment would have benefited from dose intervals >24 hours and to define the incidence of nephrotoxicity. All patients aged ≥ 16 years who had received gentamicin by EID over the 14-year period and had concentration data available were examined. End points included the numbers (%) achieving the target peak concentration [predicted maximum gentamicin concentration (C(max))] >10 mg/L, the target trough concentration at 24 hours [predicted minimum gentamicin concentration (C(min24)] <0.5 mg/L, and the target area under the curve over 24 hours of 70-100 mg/L · h. How these related to various creatinine clearance (CL(cr)) groupings was also examined, as was the number who developed nephrotoxicity (increase in creatinine of ≥ 0.04 mmol/L). After exclusions, information was available on 4523 patients. Of these, 96% achieved the target C(max), 83% the target C(min24), and 54% the target area under the curve over 24 hours. Of the 73% of patients with CL(cr) ≥ 60 mL/min, 98% and 97% achieved the target Cmax and C(min24), respectively. Of the 19% of patients with CL(cr) of 40-59 mL/min, 94% and 61% achieved the target C(max) and C(min24), respectively. Of the 8% of patients with CL(cr) of 20-39 mL/min, 83% and 15% achieved the target Cmax and C(min24), respectively. Nephrotoxicity, "probably" because of gentamicin, was observed in approximately 4% of the patients studied, which was irreversible in 25% of these (ie, 1% overall). Extending the dose interval of gentamicin to >24 hours is useful in patients with renal impairment to achieve the aims of EID. These results support initial dose intervals for gentamicin of 24, 36, and 48 hours for patients with CL(cr) ≥ 60, 40-59, and 20-39 mL/min, respectively. Irreversible nephrotoxicity was observed in approximately 1% of the patients studied.

Gentamicin arrests cancer cell growth: the intriguing involvement of nuclear sphingomyelin metabolism.

The use of gentamicin for the treatment of bacterial infection has always been an interesting and highly speculated issue for the scientific community. Conversely, its effect on cancer cells has been very little investigated. We studied the effect of high doses of gentamicin on non-Hodgkin’s T-cell human lymphoblastic lymphoma (SUP-T1). We showed that gentamicin delayed cell growth and induced cell death in lymphoma cells with a rather mild effect on lymphocytes. In SUP-T1 cells, GAPDH, B2M, CDKN1A and CDKN1B were down-expressed in comparison with lymphocytes. Gentamicin treatment in SUP-T1 cells restored the expression of GAPDH, B2M and CDKN1A to values similar to those of lymphocytes and caused overexpression of CDKN1B. The drug acted via sphingomyelin metabolism; in whole cells, sphingomyelinase activity was stimulated, whereas in purified nuclei, sphingomyelinase activity was inhibited and that of sphingomyelin-synthase was stimulated, with a consequent high level of nuclear sphingomyelin content. We suggest that the increase of nuclear sphingomyelin might enrich the nucleus of lipid microdomains that act as a platform for active chromatin and, thus, might be responsible for gene expression. It is possible that in lymphoblastic lymphoma, high doses of gentamicin induce a beneficial therapeutic outcome.

Evaluation of the effect of Boerhavia diffusa on gentamicin-induced nephrotoxicity in rats

Background:Ayurvedic literature claims that Boerhavia diffusa possesses rejuvenative properties especially related to the urinary system.Objective:To evaluate effect of aqueous extract of root of Boerhavia diffusa in gentamicin-induced nephrotoxicity in rats.Materials and Methods:Study was conducted in two parts, using 40 rats in each part. Rats were equally divided into five groups for each part. Group 1: Normal control, Group 2: Disease control and Groups 3, 4, and 5: α-lipoic acid (ALA) and 200 and 400 mg/kg of B. diffusa, respectively. All groups, except Group 1, concomitantly received gentamicin 150 mg/kg/day for 10 days. Parameters measured in part I were blood urea nitrogen (BUN), serum creatinine, kidney malondialdehyde (MDA), and glutathione (GSH) levels, kidney injury on histopathology; in part II, paraaminohippurate (PAH) clearance.Statistical Analysis:Mean ± SD of body weight, creatinine, BUN, MDA, GSH and PAH clearance were compared using parametric tests. Median histopathology scores were compared using Kruskal–Wallis test. ‘P’ value of < 0.05 was considered significant.Results:High dose of gentamicin caused significant elevation in BUN, serum creatinine and kidney MDA, fall in kidney GSH and histopathological damage in disease control group as compared with normal control (P < 0.05). Treatment with B. diffusa prevented changes in above parameters, comparable to ALA. Effects of both doses of B. diffusa were significantly better than disease control (P < 0.05).B. diffusa did not show significant improvement in PAH clearance, which was reduced due to gentamicin damage.Conclusion:B. diffusa exerted protection against structural and functional damage induced by gentamicin possibly due to its antioxidant properties.

Comparison of changes in urinary and blood levels of biomarkers associated with proximal tubular injury in rat models

To investigate useful biomarkers associated with proximal tubular injury, we assessed changes in levels of a focused set of biomarkers in urine and blood. Male rats administered a single dose or four doses of gentamicin (GM, 240 mg/kg/day) or a single dose of cisplatin (CDDP, 5 mg/kg) were euthanized on days 2 (the day after initial dosing) 5, or 12. At each time point, histopathological examination of the kidney and immunohistochemistry for biomarkers, kidney injury molecule-1 (Kim-1), lipocalin (NGAL), clusterin (CLU), cystatin C (CysC) and β2-microglobulin (β2M) were performed. Biomarker levels were measured in urine and blood. In both treatment groups, degenerated/necrotic proximal tubules and regenerated tubules were mainly observed on days 5 and 12, respectively. At the same time as these tubular injuries, urinary Kim-1, CysC and β2M levels were increased. Moreover, urinary levels of CysC and β2M in GM-treated animals and Kim-1 in CDDP-treated animals increased (on day 2) prior to tubular injury on day 5. This was considered to reflect the characteristics of drug toxicity. Although almost all of the biomarkers in blood were not sufficiently sensitive to detect proximal tubular injury, urinary and plasma β2M levels simultaneously increased. Therefore, in addition to urinary Kim-1, CysC and β2M levels, plasma β2M levels were also considered useful for detecting proximal tubular injury.

ESBL Escherichia coli Ventriculitis after Aneurysm Clipping: A Rare and Difficult Therapeutic Challenge.

Background. Extended spectrum beta-lactamase (ESBL) produced Escherichia coli (E. coli) ventriculitis is a rare infection of the central nervous system, with increasing rarity in the adult population. The therapeutic strategy to achieve cure may need to involve a combination of intraventricular and intravenous (IV) therapy. Objective. To describe a case of ESBL E. coli meningitis/ventriculitis in an adult and outline the antimicrobial therapy that leads to cure. Methods. We retrospectively reviewed the records of a patient admitted to the neurosurgical department for aneurysmal subarachnoid hemorrhage, who developed ESBL E. coli ventriculitis. Results. A 55-year-old female, admitted for a Fisher grade 3, World Federation of Neurological Surgeons grade 1, subarachnoid hemorrhage, developed ESBL E. coli ventriculitis requiring a combination of intraventricular gentamicin and high dose intravenous meropenem for clearance. Cerebrospinal fluid clearance occurred at 7 days after initiation of combined therapy. The patient remained shunt dependent. Conclusions. Meningitis and ventriculitis caused by ESBL E. coli species are rare and pose significant challenges to the treating physician. Early consideration for combined intraventricular and IV therapy should be made.

A single 80 mg intravenous gentamicin dose prior to prostate needle biopsy does not reduce procedural infectious complications.

IntroductionRates of infectious complications continue to increase following transrectal ultrasound guided prostate needle biopsy (TRUS PNB). Administration of a parenteral antibiotic at time of procedure represents one potential prophylaxis strategy. The efficacy of this practice remains incompletely defined.Material and methodsOur institutional TRUS PNB database was reviewed to identify consecutive men undergoing a biopsy over a 48-month period. The peri-operative intravenous antibiotic regimen (when used) included gentamicin 80 mg administered intravenously (IV) 30 minutes prior to biopsy. The incidence of infections post-biopsy was compared between patients receiving oral alone versus IV plus oral antibiotic prophylaxis.Results182 of 522 men (34.9%) included in this study received peri-procedural IV gentamicin at time of TRUS PNB, with a significant increase in utilization during the study time period (p <0.001). In total, 39 patients (7.5%) developed an infectious complication post-biopsy. No differences in infection rates were observed between patients receiving only oral prophylaxis (27 of 340, 7.9%) versus those receiving oral with IV gentamicin (12 of 182, 6.6%) (p = 0.73).ConclusionsIn this 4-year cohort analysis, a single peri-procedural dose of 80 mg of intravenous gentamicin failed to confer a reduction in infectious complications following prostate needle biopsy. Such data underscore the need to better understand the dose, route, and type of antimicrobial therapy to limit procedural infections.

Pharmacoepidemiology of Gentamicin Prescription in Dogs by some Practicing Veterinarians in Nigeria

The objective of this study was to evaluate the prescribing trend of gentamicin in dogs by veterinarians in Nigeria. A retrospective and cross-sectional survey was done in six geopolitical zones of Nigeria. About 150 questionnaires were administered to practicing licensed veterinarians within the study areas addressing issues such as prescribing pattern, indications, dosage regimen, therapeutic monitoring, efficacy and adverse effects of gentamicin in dogs. Data obtained was checked for its completeness and analyzed using Microsoft office Excel 2007. Gentamicin had the highest prescription rate (32%), closely followed by streptomycin (31%) and neomycin (22%). A greater percentage (59 %) of the respondents affirmed that they don’t often prescribe gentamicin. However, it is mostly prescribed for dogs with signs of gastroenteritis at a common dose of 4-5 mg/kg intramuscularly, where by 94 % of the respondents attested to its effectiveness. But 52 % of the respondents were not sure of the gentamicin dose they administer in dogs. Very few monitored their patients after treatment hence a small number of adverse effects, predominantly nephrotoxicity were observed by the respondents. Prescription pattern of gentamicin in dogs and patient monitoring is generally poor suggesting inadequate knowledge and application of pharmacology consequently the need for proper education in this subject.

Assessment of mitochondrial membrane potential in HEI-OC1 and LLC-PK1 cells treated with gentamicin and mitoquinone.

To determine the effects of concurrent treatment with gentamicin and the mitochondria-targeted antioxidant mitoquinone (MitoQ; which may prevent gentamicin ototoxicity) on change in the mitochondrial membrane potential (Δψ(m)), a precursor of apoptosis. Prospective and controlled. Academic research laboratory. LLC-PK1 (Lilly Laboratories Culture-Pig Kidney Type 1) and HEI-OC1 (House Ear Institute Organ of Corti 1) cells-renal and auditory cell lines, respectively-were used in this study. Δψ(m) was assessed by flow cytometry through the MitoProbe JC-1 Kit for Flow Cytometry in untreated LLC-PK1 and HEI-OC1 cells and cells exposed to low- (100µM) or high- (2000µM) dose gentamicin for 24 hours, with and without 0.5µM each of MitoQ or idebenone (IDB; an untargeted ubiquinone). Δψ(m) was not different in untreated LLC-PK1 cells and cells coincubated with low-dose gentamicin and MitoQ or IDB (P > .05). In HEI-OC1 cells, coincubation with low-dose gentamicin and MitoQ decreased Δψ(m) (P = .002). Coincubation of LLC-PK1 cells with high-dose gentamicin and DMSO, MitoQ, or IDB depolarized Δψ(m) (P < .0001), with MitoQ depolarizing the Δψ(m) to a greater extent than that of IDB (P = .03). In contrast, HEI-OC1 cells demonstrated a hyperpolarized Δψ(m) when coincubated with high-dose gentamicin and DMSO, MitoQ, or IDB (P < .001). The combination of gentamicin and MitoQ holds the potential to disrupt Δψ(m). This suggests a heightened need to monitor for toxicity in patients receiving both agents.

Gentamicin trough levels using a simplified extended-interval dosing regimen in preterm and term newborns.

To evaluate a simplified gentamicin extended-interval dosing regimen in a large cohort of preterm and term newborns, we conducted a retrospective cohort study over a 4-year period. All inborn newborns who received gentamicin for the first episode of suspected or proven sepsis were eligible. Newborns received 4 mg/kg gentamicin intravenously 24-hourly, except for those at <28 weeks of gestation who received gentamicin 36-hourly. Trough levels were taken before the third dose and considered non-toxic if ≤2 μg/mL. Infants were analysed in gestational age subgroups: <28 weeks, 28-31 weeks, 32-35 weeks, 36-39 weeks and ≥40 weeks. Newborns who received indomethacin co-medication were analysed separately. Nine hundred ninety-three newborns, gestational age range 23(+2)-42(+1) weeks, birth weight range 397-5936 g, were included. The median (interquartile range (IQR)) gentamicin trough level for all newborns was 1.3 μg/mL (0.8-1.7). Ninety per cent of newborns had non-toxic trough levels. The incidence of trough levels >2 μg/mL was between 2.2 and 9.7 % in all subgroups except for infants born at 28-31 weeks of gestation, where 21.7 % of trough levels were >2 μg/mL. Indomethacin co-medication significantly increased the median gentamicin trough level in preterm infants at <32 weeks of gestation. This study demonstrates that simplified gentamicin dosage regimens are feasible. Prospective evaluations are required to establish safety profiles.

Spontaneous and Partial Repair of Ribbon Synapse in Cochlear Inner Hair Cells After Ototoxic Withdrawal.

Ototoxicity is one of the major causes of sensorineural deafness. However, it remains unclear whether sensorineural deafness is reversible after ototoxic withdrawal. Here, we report that the ribbon synapses between the inner hair cells (IHCs) and spiral ganglion nerve (SGN) fibers can be restored after ototoxic trauma. This corresponds with hearing restoration after ototoxic withdrawal. In this study, adult mice were injected daily with a low dose of gentamicin for 14 consecutive days. Immunostaining for RIBEYE/CtBP2 was used to estimate the number and size of synaptic ribbons in the cochlea. Hearing thresholds were assessed using auditory brainstem responses. Auditory temporal processing between IHCs and SGNs was evaluated by compound action potentials. We found automatic hearing restoration after ototoxicity withdrawal, which corresponded to the number and size recovery of synaptic ribbons, although both hearing and synaptic recovery were not complete. Thus, our study indicates that sensorineural deafness in mice can be reversible after ototoxic withdrawal due to an intrinsic repair of ribbon synapse in the cochlea.

Effect of gentamicin on the auditory analyzer in sexually immature animals.

Auditory function of immature rabbits was evaluated using two electrophysiological methods, brainstem auditory evoked response (BAER) and distortion product otoacoustic emission (DPOAE), in chronic experiments following administration of therapeutic doses of gentamicin. Impairment of auditory function manifested in increased thresholds and decreased amplitude of the 1st BAER peak was established. DPOAE parameters were not significantly changed. It was suggested that gentamicin decreased activity of spiral ganglion neurocytes in animals with immature auditory analyzer.

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.

Predictive performance of a gentamicin population pharmacokinetic model in neonates receiving full-body hypothermia.

Population pharmacokinetic (popPK) models derived from small pharmacokinetics (PK) studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated. A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (University of California-San Francisco) data set. The predictive performance of this model was evaluated in an external retrospective data set from the University of California-San Francisco (validation A) and another from Duke University (validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions. Forty-one neonates (n = 18 validation A; n = 23 validation B) with median (range) gestational age of 40 weeks (33-42) and birth weight of 3.3 kg (1.9-4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36 hours after dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (validation A; median average fold error = 1.1 and numerical prediction distribution error P > 0.05) but underpredicted concentrations from the outside institution (validation B; median average fold error = 0.6 and numerical prediction distribution error P < 0.05). The model demonstrated adequate predictive performance for an external data set in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies.

A rapid change in a patient's chest radiograph appearances

A 72-year-old man with a history of rheumatoid arthritis (on multiple immunosuppressants: leflunomide, etanercept and hydroxychloroquine) was admitted with headache and fever. He had no other symptoms or relevant medical...

Assessment of Mitochondrial Function and Membrane Potential in PK1 Cells Treated with Gentamicin and MitoQ

Objectives: Determine the effects of concurrent treatment with the aminoglycoside antibiotic gentamicin and mitoquinone (MitoQ), a mitochondria-targeted derivative of the antioxidant ubiquinone that may protect against aminoglycoside ototoxicity, on mitochondrial function and membrane potential. Methods: This study was prospective and controlled. Mitochondrial membrane potential (MMP) was assessed by flow cytometry using MitoProbeTM JC-1 Kit in untreated PK1 cells and cells exposed to low (100 µM) or high (2000 µM) dose gentamicin for 24 hours, with and without 0.5 µM each of MitoQ or idebenone (an untargeted ubiquinone). Mitochondrial function was determined using the Seahorse XF-24TM flux analyzer. Results: MMP was not different in untreated cells and cells co-incubated with low-dose gentamicin and MitoQ or idebenone ( P &gt; .05). Co-incubation with high-dose gentamicin and MitoQ or idebenone decreased MMP ( P &lt; .0001), with MitoQ co-incubation decreasing MMP to a greater extent compared with idebenone ( P = .0001). Basal oxygen consumption rate (OCR) was not different between treatments ( P = .15). Maximal OCR was not different between untreated cells and cells treated with MitoQ alone, low dose gentamicin alone, or the combination of MitoQ and low dose gentamicin ( P &gt; .05). In contrast, cells treated with high dose gentamicin and in combination with MitoQ have reduced maximal OCR ( P = .037 and .026). Conclusions: The combination of gentamicin and MitoQ holds the potential to disrupt mitochondrial function and membrane potential. This suggests a heightened need to monitor for toxicity in patients receiving both agents.

Predictive performance of gentamicin dosing nomograms

BackgroundSeveral nomograms have been proposed to facilitate the determination of initial gentamicin dosing regimens in clinical settings. This study aimed to assess the predictive performance of these nomograms in Korean patients.MethodsGentamicin concentrations were determined in 84 patients with infective endocarditis (IE) and in 95 patients with other infections. All patients underwent therapeutic drug monitoring in Seoul National University Hospital from 2006 to 2012. Individual pharmacokinetic parameters were estimated using a Bayesian method, which predicted steady state peak and trough serum concentrations. Six nomograms were evaluated in patients with “other” infections: the Thomson guidelines, Hull-Sarubbi table, and Rule of Eights, for multiple daily dosing; and the Hartford nomogram, Barnes-Jewish Hospital nomogram, and Sanford Guide, for extended-interval dosing. In IE patients, synergistic combination dosing nomograms, based on the American Heart Association dosing interval guidelines, were evaluated.ResultsGentamicin dosing nomograms performed poorly in attaining the target peak serum concentrations. Multiple-daily dosing nomograms predicted peak serum gentamicin concentrations better than did the extended-interval dosing nomograms (31.9%–72.3% vs 4.3%–45.7%, respectively). Similarly, in patients with IE, the once-daily dosing nomogram resulted in a significantly lower percentage of patients achieving target peak gentamicin concentrations than that associated with the thrice-daily dosing nomogram (P=0.0015). All of the multiple-daily dosing, extended-interval dosing, and synergistic combination dosing nomograms predicted the nontoxic target trough concentrations in >80% of patients.ConclusionGentamicin dosing nomograms performed poorly in achieving the target peak serum concentrations. New gentamicin nomograms may be required in patients with IE, particularly for once-daily dosing. Therapeutic drug monitoring is highly recommended for gentamicin to ensure that the target concentrations are achieved.