Dose Of Gentamicin Research Articles

Cost-effectiveness of a bone substitute delivering gentamicin in the treatment of chronic osteomyelitis of long bones: Protocol for the CONVICTION randomized multicenter study.

Chronic osteomyelitis is a serious osteoarticular infection that most often occurs in the long bones, responsible for significant morbidity with the risk of fracture and amputation. Despite advances in both antibiotics and surgical treatment, the probability of recurrence of infection remains at around 20%. Cerament-G (BONESUPPORT AB, Sweden) is a synthetic bone substitute that fills the bone void left by surgery, prevents infection and promotes bone regeneration within this space. Cerament-G also provides the local delivery of high doses of gentamicin over several weeks. Two prospective observational studies described a number of infectious recurrences of 4 and 5% after the use of Cerament-G. Although available in France, Cerament-G is currently not reimbursed and its high cost constitutes a barrier to its use. We hypothesize that the use of Cerament-G will lead to fewer costs to the collectivity while improving patient utility and, as an innovative strategy, will be superior to standard of care on recurrence of infection. The Conviction Study is a prospective, multicenter, randomized, single blind study conducted in 14 French Reference Centers for Complex Osteoarticular infections. The main objective is to evaluate the cost-effectiveness of using Cerament-G in the treatment of chronic long bone osteomyelitis by comparing this innovative strategy to standard of care. A cost-utility analysis from the collective perspective will be conducted over a 24-month time horizon after the initial surgery. The outcome for the main medico-economic evaluation will be Quality Adjusted Life Years (QALYs). The study is being conducted throughout the CRIOAc network in France, in referral centers for the management of complex infections which will facilitate patient recruitment. This study has several limitations: the investigators have to be trained to handle the device, and it was impossible to blind the surgeon. If the use of Cerament-G is demonstrated to be superior to leaving the dead space empty during surgery for patients with stage III chronic long bone osteomyelitis, its use will be recommended to improve the prognosis of such patients, and this device may eventually qualify for reimbursement through the French Health Insurance scheme. This protocol received authorization from the Ethics Committee CPP Sud Méditerranée V on April 27, 2021 (21.03.10.77652) and the French National Agency for Medicines and Health Products on May 6, 2021 (2020-A02299-30). Results will be disseminated to the scientific community through congresses and publication in peer-reviewed journals.

Effect of Volumes of Solutions on Intraocular Pressure During Intravitreal Injection of Low Dose Gentamicin in Horses With Recurrent Uveitis: A Randomized Controlled Study.

Horses with recurrent uveitis can be treated by intravitreal injection of low dose gentamicin under sedation and after local anesthetic techniques including the retrobulbar nerve block. Since it is reported that retinal degeneration can be secondary to an acute increase of intraocular pressure (IOP), the current randomized controlled study was carried out in order to investigate the changes in IOP following retrobulbar anesthesia, with two different volumes of local anesthetic (lidocaine) solution (10 and 5 mL), and intravitreal injection of 6 mg gentamicin in two different volumes of solution (0.3 and 0.15 mL). Multivariate regression showed that IOP was significantly lower in the pathologic eye at baseline (estimated effect size -6.1 mmHg; P=.0001) and after sedation (estimated effect size -9.4 mmHg; P < .0001). The IOP was significantly higher after a 10 mL block (P .0002) but this effect was very small (+0.5 mmHg). There was no significant difference in IOP after the injection of 0.15 or 0.3 mL solution of gentamicin. There was no significant combined effect of the volume of local anesthetic used for the block and the volume of the gentamicin solution. Since the expected anesthetic effects (desensitization and akinesia) were met in all cases, the smaller volume of 5 mL of lidocaine solution would be preferable for retrobulbar block for intravitreal injections, while intravitreal injections volumes of 0.15 and 0.30 mL can be used indifferently.

Astaxanthin- Enriched Fraction from the Microalga Haematococcus pluvialis Mitigates Kidney Injury via Modulation of Nrf2/Keap1 and MAPK/ERK Pathways in Rats

Acute kidney injury is a complication of using gentamicin in high doses and is associated with severe morbidity and mortality. Astaxanthin, the red xanthophyll carotenoid pigment, has an antioxidant power higher than 100 times that of vitamin E and 10 times more than that of β-carotene, making it one of the strongest bioactive carotenoids. Haematococcus pluvialis, Haematococcaceae, microalga produces high amounts of astaxanthin in the form of astaxanthin esters besides adequate amounts of free astaxanthin. We attempted to explore the potential therapeutic effects of astaxanthin- and astaxanthin ester–enriched fractions from H. pluvialis against acute kidney injury induced by gentamicin and their mechanisms of action in rats. Adult male Wister albino rats were injected with gentamicin (100 mg/kg, i.p.) for seven consecutive days to induce acute kidney injury, and these rats were treated daily with astaxanthin ester–enriched fractions (30 mg/kg; p.o.) for 14 days. LC/ESI–MS analysis revealed the presence of different isomers of free astaxanthin, astaxanthin monoesters, and astaxanthin diesters in the astaxanthin- and astaxanthin ester–enriched fractions. Astaxanthin and its esters ameliorated kidney dysfunction, modulated nuclear factor erythroid 2 related factor 2/Kelch-like erythroid associated protein 1/hypoxia-inducible factor-alpha, and suppressed mitogen-activated protein kinases/extracellular signal-regulated kinases/renin-angiotensin system expression. Astaxanthin and its ester improved early acute kidney injury via modulation of the Nrf2/Keap1 antioxidant defense pathway and MAPK/ERK signaling cascade.Graphical

Gentamicin in Neonates with Hemodynamically Significant Patent Ductus Arteriosus.

Gentamicin has been shown to cause vasodilation in preclinical studies. Hemodynamically significant patent ductus arteriosus (hsPDA) is a commonly observed congenital heart disorder in preterm neonates. Concomitant gentamicin theoretically shall delay the closure/result in nonclosure of ductus arteriosus (DA). Similarly, hsPDA can alter the pharmacokinetics of gentamicin and so trough gentamicin concentrations. We carried out the present study to evaluate the association between gentamicin use and closure of hsPDA (treated with acetaminophen) as well as the effect of hsPDA on trough concentrations. This study was a prospective, observational study that included 60 neonates diagnosed with hsPDA by echocardiography and 102 neonates without hsPDA. Demographic details, size of DA as per echocardiography at the end of treatment with acetaminophen, gentamicin-dosing regimen, and trough concentrations were collected. Standard definitions were adhered in classifying the gestational age, birth weights, and size of DA. The numerical values are reported in median (range). Neonates with hsPDA had significantly lower daily doses of gentamicin [4.5 (2.5-10), 7 (3.2-13) mg; P < 0.001] but longer duration of therapy [8 (3-14), 5 (3-7) days; P < 0.001] than those without hsPDA in very preterm neonates. No significant differences were observed in the trough concentrations of gentamicin between the groups. No association was observed between gentamicin use and closure of DA. However, those with successful closure of DA received gentamicin for a longer duration [6 (3-10), 4 (3-14) days; P < 0.05] that was independent of acetaminophen duration and had received higher cumulative doses of gentamicin. In conclusion, we observed a significantly longer duration of gentamicin therapy in neonates with hsPDA compared to those without hsPDA. No significant differences were observed in the rates of closure of DA with concomitant gentamicin administration and gentamicin trough concentrations.

Targeting Lower Serum Trough Concentrations: A New Gentamicin Dosing Strategy for Suspected Neonatal Early-Onset Sepsis.

Neonatal gentamicin dosing algorithms are not designed to achieve serum trough concentrations ≤1 mcg/mL. The purpose of our study was to evaluate a new gentamicin algorithm based on serum creatinine (SCr) and gestational age (GA) designed to achieve serum gentamicin trough concentrations ≤1 mcg/mL. A retrospective cohort study was conducted in a level IIIB neonatal intensive care unit. The incidence of elevated serum gentamicin troughs for this study was compared with the center's previously published results to evaluate the proposed dosing algorithm. Patients were included if gentamicin was administered within the first 7 days of life and a serum gentamicin trough concentration and a baseline SCr concentration were obtained. Patients were further subdivided into groups based on GA for data analysis: ≤30 weeks (group 1), 30-34 weeks (group 2), and ≥35 weeks (group 3). The SCr was considered mildly elevated (0.81-0.99 mg/dL) or elevated (≥1 mg/dL). The respective outcomes between the post-algorithm and control groups were examined using intention-to-treat analysis and Bayesian modeling to calculate rate differences. Of the 2377 patients evaluated, 366 met the inclusion criteria. Significantly lower percentages of elevated serum gentamicin troughs were noted in groups 2 and 3 subsequent to the implementation of the dosing algorithm with 16% and 15% lower rate differences, respectively. Regardless of GA, there were significantly fewer elevated serum troughs in the post-implementation groups than in the control with mildly elevated and elevated SCr p < 0.001. Using a dosing algorithm based on SCr significantly reduced the number of elevated serum trough rates in neonates with a GA greater than 30 weeks.

Detekcija rezistencije na antibiotike i kapsularnih tipova streptokoka grupe B izolovanih u vaginalnom brisu trudnica

Introduction: Group B streptococcus (GBS) is an opportunistic pathogen that colonizes the gastrointestinal and genital tract of 10 - 30% of healthy people. It can cause early or late-onset neonatal disease manifested as pneumonia, sepsis, and meningitis. Penicillins are the first-choice therapy and prophylaxis of mother-to-child transmission. In the case of penicillin allergy, macrolides or vancomycin are used. Aim: The objectives of study were to determine antimicrobial susceptibility and macrolides resistance phenotypes of GBS isolates, as well as to determine capsular types (CPS) and detection of hypervirulent ST17 clone. Material and methods: From January 1st to December 31st 2021, 134 GBS isolates were collected from vaginal swabs of pregnant women. Identification was performed using conventional microbiological methods and molecular detection of species-specific dltR gene. The disk diffusion method was used to test antibiotic resistance according to EUCAST standards. Capsular typing was conducted by multiplex PCR method. A hypervirulent ST17 clone was identified by the detection of the hvgA gene using PCR. Results: All isolates were susceptible to penicillin, vancomycin, and fluoroquinolones. Tetracycline resistance was the most common, detected in 81.3% (109/134) strains. Macrolide resistance was detected in 3.3% (50/134) of isolates, while 14.9% (20/134) showed resistance to high doses of gentamicin. Resistance to chloramphenicol was noticed in 1.5% (2/134) isolates. The most common macrolide resistance phenotype was cMLS (31/50, 62.0%). The most identified CPS were V found in 33 isolates (25.0%) and III identified in 30 strains (22.0%). A hypervirulent ST17 clone was detected in 12.7% (17/134) of isolates; 15 belonged to CPS III and 2 to CPS IV. Conclusion: The high frequency of macrolide resistance in group B streptococci isolated from colonized pregnant women is a severe public health concern. Also, the detection of numerous CPS III isolates and ST17 clones indicates the need for continuous screening and monitoring of the prevalence of GBS infections in pregnant women and neonates.

Investigation of the protective effect of Tarantula cubensis extract on the liver and brain of rats exposed to gentamicin

This study aimed to investigate the possible protective effects ofTarantula cubensisextract (TCE) on the liver and brain of rats exposed to gentamicin (GM). A total of 40 male Sprague Dawley rats were randomly divided into four equal groups: control, TCE, GM, and GM+TCE. Some biochemical indices, apoptotic markers (B-cell lymphoma 2 [Bcl-2] and Bcl-2 associated X protein [Bax]) and histopathological changes were evaluated. In the GM group, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin, brain and liver tissue malondialdehyde (MDA) concentrations increased; albumin, total protein, brain and liver tissue superoxide dismutase (SOD) concentrations and the total antioxidant status (TAS) decreased. Apoptosis induced down-regulation of Bcl-2 and up-regulation of Bax in liver and brain tissues in the GM group. GM-treated animals demonstrated several histopathological changes. TCE administration restored some histopathological changes. Lipid peroxidation and apoptosis decreased, antioxidant defense increased, concentrations of some serum biochemical indices (AST, ALT, ALP, GGT, and total bilirubin) decreased, and albumin and total protein levels increased in the TCE+GM group compared to the GM group. In conclusion, high doses of GM induce adverse effects on liver and brain tissue of rats. It was concluded that TCE administration can improve these adverse effects by reducing lipid peroxidation and apoptosis, improving the antioxidant defense system. TCE can be used to protect against the toxic effect of GM and other chemical agents in the liver and brain in veterinary medicine. However, additional studies are needed to confirm this assumption.

Does addition of gentamicin for antibiotic prophylaxis in total knee arthroplasty reduce the rate of periprosthetic joint infection?

First-generation cephalosporins are used as antibiotic prophylaxis in total joint arthroplasty patients. However, this regimen does not address Gram-negative bacteria causing periprosthetic joint infection (PJI). Previous studies have suggested that the addition of an aminoglycoside as antibiotic prophylaxis in THA reduces surgical site infection (SSI), and less is known on its effect in TKA. This study aimed to investigate if the addition of a single-dose gentamicin, administered pre-operatively, is associated with lower rates of infection in TKA patients. This is a retrospective study of patients who underwent primary TKA as treatment for osteoarthritis between January 2011 and April 2021, with a minimum 1-year follow-up. The mean age was 69.9 (± 9.8), the mean BMI was 29.7 (± 5.5), and most patients had American Society of Anaesthesiology (ASA) score of 2-3 (92.9%). Patients were stratified based on the peri-operative antibiotic prophylaxis they received: cefazolin with addition of gentamicin (case group) or cefazolin (control group). Our primary study endpoints were rates of PJI and SSI, which were compared between groups using the chi-square test. Statistical significance was set as p < 0.05. The final study population consisted of 1590 patients, 1008 (63.4%) in the control group and 582 (36.6%) patients in the case group. The total infection rate for patients that received gentamicin dropped by 34%; however, this finding did not reach statistical significance (1.3% (control) vs. 0.86% (case), p = 0.43). The same drop was seen after subdivision of infections to PJI (0.5% vs. 0.34%, 32% drop, p = 0.66) and SSI (0.8% vs. 0.52%, 35% drop, p = 0.52). A single dose of gentamicin administered pre-operatively to a standard antibiotic prophylaxis was not associated with a statistically significant lower rate of PJI. Although the difference in infection rate did not reach statistical significance, the current study noted a drop in the rate of infection by 1/3 in the gentamicin cohort. Further investigation to evaluate the potential benefit of adding gentamicin to a peri-operative antibiotic regimen is warranted.

Zamzam Water Ameliorates Gentamicin-Induced Testicular Toxicity in a Rat Model via Targeting Sperm Parameters, Testicular Tissue Oxidative Insult, Inflammation, Apoptosis, and Pituitary-Gonadal Axis.

Gentamicin is considered one of the most typical causes of testicular damage. Oxidative stress is a significant contributor to testicular tissue damage. Zamzam water (alkaline in nature) has an antioxidant effect. The purpose of this study was to assess the potential palliative effect of Zamzam water against gentamicin-induced testicular damage. Thirty Rats were separated into three groups, each with ten rats, as follows: The Control received only normal saline. The gentamicin group received 100 mg/kg/day of gentamicin intraperitoneally for six days from day 15 to the end of the experiment. The gentamicin +Zamzam Water group received a dose of gentamicin 100 mg/kg/day intraperitoneally with Zamzam water as their sole source of drinking from day one to day 21. Hormonal assay in serum, histological, immunohistochemical, and ultrastructural examination of testicular tissue with a molecular study were obtained. Pretreatment with Zamzam water significantly p < 0.001 increased serum levels of testosterone, FSH, and LH, as well as the percentage of sperm motility and progressive motility. It also upregulated SOD, CAT, GPx enzymatic activity, gene expression of Nrf2/HO-1, and immunoexpression of PCNA. While the percentage of dead sperm and abnormal sperm, immunoexpression of NFκB, Caspase 3, inflammatory cytokines TNFα, IL-1β, IL-6, and MDA levels significantly (p < 0.001) declined with histological improvement. It was concluded that Zamzam water as alkaline water possesses antioxidant, anti-inflammatory, and antiapoptotic effects against gentamicin-induced testicular toxicity in vivo.

Nephroprotective Activity of Green Microalgae, Chlorella sorokiniana Isolated from Jordanian Water

Nephropathy is a global health issue that affects more than 20% of the adult population. Nephropathy is expected to be the fifth leading cause of death worldwide over the coming two decades. The introduction of green microalgae in nutrition and therapeutics for their biological activities is increasing. The current study examined the effect of Chlorella sorokiniana on renal health after inducing nephrotoxicity in mice. Preliminary screening of the algal aqueous extract revealed the presence of soluble polyphenols and triterpenoids. Successive intraperitoneal doses of gentamicin were administered to mice to induce nephrotoxicity. Concurrent intraperitoneal doses of the algal extract were administered to the infected mice to evaluate their nephroprotective activity. Two different concentrations of the treatment agent were administered in successive doses to two groups of mice. The tested concentrations were 150 and 300 mg/kg of mouse weight, respectively. The other two groups were either left untreated (normal control) or treated only with antibiotics (negative control). Creatinine, urea, and uric acid levels were analyzed in both serum and urine samples to evaluate the renal health of each animal group. Histochemical examination of the renal tissues was performed to assess the damage and improvement status. In vivo studies revealed a promising and significant nephroprotective activity of C. sorokiniana.

Impact of Fractionated Gentamicin Dosing on Induction of Nephrotoxicity: An Experimental Study in Rats.

Impact of Fractionated Gentamicin Dosing on Induction of Nephrotoxicity: An Experimental Study in Rats.

Physiologically-based pharmacokinetic modelling and dosing evaluation of gentamicin in neonates using PhysPK.

Each year, infections caused around the 25% of neonatal deaths. Early empirical treatments help to reduce this mortality, although optimized dosing regimens are still lacking. The aims were to develop and validate a gentamicin physiologically-based pharmacokinetic (PBPK) model and then potentially explore dosing regimens in neonates using pharmacokinetic and pharmacodynamic criteria. The PBPK model developed consisted of 2 flow-limited tissues: kidney and other tissues. It has been implemented on a new tool called PhysPK, which allows structure reusability and evolution as predictive engine in Model-Informed Precision Dosing (MIPD). Retrospective pharmacokinetic information based on serum levels data from 47 neonates with gestational age between 32 and 39 weeks and younger than one-week postnatal age were used for model validation. The minimal PBPK model developed adequately described the gentamicin serum concentration-time profile with an average fold error nearly 1. Extended interval gentamicin dosing regimens (6 mg/kg q36h and 6 mg/kg q48h for term and preterm neonates, respectively) showed efficacy higher than 99% with toxicity lower than 10% through Monte Carlo simulation evaluations. The gentamicin minimal PBPK model developed in PhysPK from literature information, and validated in preterm and term neonates, presents adequate predictive performance and could be useful for MIPD strategies in neonates.

Republication de : Central nystagmus and alterations in vestibular tests due to an inadvertent gentamicin administration into spinal space: A CARE case report

Gentamicin has a well-known potential for damaging the peripheral vestibular organs. However, it is considered to be innocuous to the CNS as it crosses the blood-brain barrier poorly. Here, we describe central neuro-otological abnormalities developed by a patient after deployment of gentamicin into his spinal space. A 61-year-old male unintentionally received gentamicin during spinal locoregional anesthesia for a urological procedure. During the first 48 hours the patient presented upper extremity dysmetria, dysarthria, and bilateral abducens nerve paralysis from which he recovered completely. He remained asymptomatic from day 3 to 10 after the incident. On day 11 he presented an acute vestibular syndrome. Severe bilateral vestibulopathy was confirmed by means of video head impulse testing. From day 14 onwards, he presented a persistent horizontal left-beating nystagmus, showing no variation or signs of compensation after 14 months, not responding to intensive vestibular rehabilitation or vestibular suppressant drugs. During follow-up, intercurrent gaze-evoked/direction-changing nystagmus has been recorded in various opportunities. We interpreted these findings as signs of both severe peripheral bilateral vestibulopathy and cerebellar and/or midbrain late-onset neurotoxicity, which can be explained by the intrinsic neurotoxic capability of high doses of gentamicin in the CNS.

A Prospective Study on the Vestibular Toxicity of Gentamicin in a Clinical Setting.

Gentamicin is a widely used aminoglycoside with ototoxicity as a known adverse effect. Because of the difficulty in clinical recognition, the prevalence of gentamicin ototoxicity in practice is thought to be higher than reported. This study aimed to prospectively assess the effect of gentamicin on vestibular function and whether ototoxicity is underrecognized. Single-center, prospective, nonblinded trial. Inpatient tertiary hospital setting followed by vestibular outpatient clinic review. Forty-eight patients undergoing a urologic procedure were recruited, with 24 and 17 patients having one or two follow-up tests, respectively, after initial gentamicin administration. Single dose of gentamicin during a urologic procedure. Gains for the vestibuloocular reflex (VOR) were measured using the video head impulse test before receiving gentamicin and at two other timepoints after gentamicin. The gains in VOR were then compared with previous testing sessions to determine if there was a deterioration after gentamicin use. Before receiving gentamicin, the gains for horizontal VOR were measured for 48 patients. The gains were measured a second time for 24 patients at varying durations postgentamicin (1-56 d) and a third time for 17 patients (14-152 d) postgentamicin. The mean VOR gain for Timepoints 1, 2, and 3 were 0.72 ± 0.13, 0.75 ± 0.16, and 0.79 ± 0.18, respectively. Linear-mixed model with repeated-measure analysis revealed no significant difference in VOR gain between Timepoints 1 and 2 ( p = 0.19). There was no significant effect observed on mean VOR gain decrement after a single dose of gentamicin.

629 Improving Gentamicin Prescribing for Intra-Abdominal Sepsis on a General Surgical Firm

Abstract Aim Gentamicin is recommended by local guidelines for the empirical treatment of intra-abdominal sepsis. However, severe side effects that can occur through prolonged raised through levels requires its use through a specific dosing protocol. Challenges of this means it often “falls off” the drug chart, leading to suboptimal drug-levels. The aim of this quality improvement project was to improve the process of gentamicin prescription. Method A two-week retrospective analysis of all patients admitted was performed to obtain baseline data. Information was collected on gentamicin use, if levels were taken at 6–14 hours post-dose, and if subsequently correctly re-prescribed. PDSA 1 involved placing posters in the surgical office, reminding the clerking doctor of the gentamicin protocol. PDSA 2 involved a departmental teaching session to reiterate the above intervention. Results At baseline, only 7% (1/15) of patients prescribed gentamicin had a correct post-dose level taken and subsequently received a correct second dose. After PDSA 1, this rose to 67% (2/3). After PDSA 2, this level was similar at 60% (3/5). Furthermore, at baseline 47% (15/32) of patients deemed to have intra-abdominal sepsis received gentamicin. After PDSA 1, this proportion fell to 11% (3/28) and after PDSA 2 this was 38% (5/13). Conclusions Education sessions and posters were effective at increasing the proportion of patients that received a safely prescribed second dose of gentamicin, as a result of correctly taken trough levels. However, a reduction in the percentage of patients receiving gentamicin for intra-abdominal sepsis possibly suggests further education on the role of gentamicin is required.

EP-574 Improving gentamicin prescribing for intra-abdominal sepsis on a general surgical firm

Abstract Aim Gentamicin is recommended by local guidelines for the empirical treatment of intra-abdominal sepsis. However, severe side effects that can occur through prolonged raised trough levels requires its use through a specific dosing protocol. Challenges of this means it often “falls off” the drug chart, leading to suboptimal drug-levels. The aim of this quality improvement project was to improve the process of gentamicin prescription. Methods A two-week retrospective analysis of all patients admitted was performed to obtain baseline data. Information was collected on gentamicin use, if levels were taken at 6–14 hours post-dose, and if subsequently correctly re-prescribed. PDSA 1 involved placing posters in the surgical office, reminding the clerking doctor of the gentamicin protocol. PDSA 2 involved a departmental teaching session to reiterate the above intervention. Results At baseline, only 7% (1/15) of patients prescribed gentamicin had a correct post-dose level taken and subsequently received a correct second dose. After PDSA 1, this rose to 67% (2/3). After PDSA 2, this level was similar at 60% (3/5). Furthermore, at baseline 47% (15/32) of patients deemed to have intra-abdominal sepsis received gentamicin. After PDSA 1, this proportion fell to 11% (3/28) and after PDSA 2 this was 38% (5/13). Conclusion Education sessions and posters were effective at increasing the proportion of patients that received a safely prescribed second dose of gentamicin, as a result of correctly taken trough levels. However, a reduction in the percentage of patients receiving gentamicin for intra-abdominal sepsis possibly suggests further education on the role of gentamicin is required.

849 Optimization of intravenous gentamicin to restore functional laminin 332 in junctional epidermolysis bullosa patients harboring nonsense mutations

Junctional epidermolysis bullosa (JEB) is an incurable and fatal inherited blistering skin disease most commonly caused by nonsense mutations in LAMA3, LAMB3, or LAMC2 genes. These mutations impair the ability to produce functional laminin 332, needed for epidermal-dermal adherence. Previously, we demonstrated that intravenous (IV) gentamicin daily at 7.5 mg/kg for two weeks promoted readthrough of nonsense mutations and produced functional laminin 332. Here, we determined if treating the patients with higher gentamicin doses and more prolonged treatment would induce more functional laminin 332, and provide more long-term clinical improvement.

Vitexin alters Staphylococcus aureus surface hydrophobicity to obstruct biofilm formation

Cell Surface hydrophobicity is one of the determinant biophysical parameters of bacterial aggregation for being networked to form a biofilm. Phytoconstituent, like vitexin, has long been in use for their antibacterial effect. The present work demonstrates the role of vitexin in modulating Staphylococcus aureus surface hydrophobicity while aggregating to form biofilm and pathogenesis in a host. In planktonic form, vitexin shows minimum inhibitory concentration at 252 µg/ml against S. aureus. Sub-MIC doses of vitexin and antibiotics (26 µg/ml of vitexin, 55 µg/ml of azithromycin, and 2.5 µg/ml of gentamicin) were selected to treat S. aureus. Dead cell counts after treatment were studied through flow cytometry. As dead cell counts were minimal (<5 %), these doses were considered for all subsequent experiments. While studying aggregating cells, it was observed that vitexin reduces S. aureus surface hydrophobicity and membrane permeability at the sub-MIC dose of 26 µg/ml. The in silico binding analysis showed a higher binding affinity of vitexin with surface proteins (IcaA, DltA, and SasG) of S. aureus. Down-regulation of dltA and icaAB expression, along with the reduction in membrane potential with a sub-MIC dose of vitexin, explains reduced S. aureus surface hydrophobicity. Vitexin was found to interfere with S. aureus biofilm-associated protein biomass, EPS production, and swarming movement. Subsequently, the suppression of proteases production and down-regulation of icaAB and agrAC gene expression with a sub-MIC dose of vitexin explained the inhibition of S. aureus virulence in vitro. Besides, vitexin was also found to potentiate the antibiofilm activity of sub-MIC doses of gentamicin and azithromycin. Treatment with vitexin exhibits a protective response in S. aureus infected macrophages through modulation of expression of cytokines like IL-10 and IL-12p40 at protein and mRNA levels. Furthermore, CFU count and histological examination of infected mouse tissue (liver and spleen) justify the in vivo protective effect of vitexin from S. aureus biofilm-associated infection. From this study, it can be inferred that vitexin can reduce S. aureus surface hydrophobicity, leading to interference with aggregation at the time of biofilm formation and subsequent pathogenesis in a host.

Assessment of the Quality of Injectable Antibiotics in Benin.

Substandard and falsified medicines are an enormous threat to global health. Poor quality antibiotic preparations contribute to the development of antimicrobial resistance. In surgery, where the occurrence of healthcare-associated infections is high, healthcare teams need to rely on the quality of antibiotic prophylaxis to prevent infections. We assessed the quality of antibiotics used for surgical infection prophylaxis in Benin. Thirty-three samples were collected from six hospitals located in various departments in Benin. The antibiotics (powders for injection: amoxicillin + clavulanic acid, ampicillin, ceftriaxone; solutions for injection: ciprofloxacin, gentamicin, metronidazole) were assessed using visual inspection, pharmacotechnical tests (including uniformity of mass, pH measure, sterility test, and active pharmaceutical ingredient identification), and assay tests (including a simple analytical method thin layer chromatography) and complex analytical techniques (ultraviolet-visible spectrophotometry, high-performance liquid chromatography-diode-array detection, conductometry). Because the material needed for the methods recommended by the pharmacopeias to assess the dosage of gentamicin was not available, we developed and validated a conductometry method. Results showed that 97% (n = 32) of the samples passed visual inspection; 100% (n = 33) of the samples passed the pharmacotechnical tests, identification of active ingredients, and sterility test; 88% (n = 29) passed the test for percentage of active pharmaceutical ingredients. Overall, 15% of the samples did not pass the quality test (3% on visual inspection and 12% for excess active ingredients). Although most of the samples passed the quality tests, it appears important to perform routine quality control for intravenous medicines.

Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review.

Gentamicin is an aminoglycoside antibiotic with a small therapeutic window that is currently used primarily as part of short-term empirical combination therapy. Gentamicin dosing schemes still need refinement, especially for subpopulations where pharmacokinetics can differ from pharmacokinetics in the general adult population: obese patients, critically ill patients, paediatric patients, neonates, elderly patients and patients on dialysis. This review summarizes the clinical pharmacokinetics of gentamicin in these patient populations and the consequences for optimal dosing of gentamicin for infections caused by Gram-negative bacteria, highlighting new insights from the last 10 years. In this period, several new population pharmacokinetic studies have focused on these subpopulations, providing insights into the typical values of the most relevant pharmacokinetic parameters, the variability of these parameters and possible explanations for this variability, although unexplained variability often remains high. Both dosing schemes and pharmacokinetic/pharmacodynamic (PK/PD) targets varied widely between these studies. A gentamicin starting dose of 7 mg/kg based on total body weight (or on adjusted body weight in obese patients) appears to be the optimal strategy for increasing the probability of target attainment (PTA) after the first administration for the most commonly used PK/PD targets in adults and children older than 1 month, including critically ill patients. However, evidence that increasing the PTA results in higher efficacy is lacking; no studies were identified that show a correlation between estimated or predicted PK/PD target attainment and clinical success. Although it is unclear if performing therapeutic drug monitoring (TDM) for optimization of the PTA is of clinical value, it is recommended in patients with highly variable pharmacokinetics, including patients from all subpopulations that are critically ill (such as elderly, children and neonates) and patients on intermittent haemodialysis. In addition, TDM for optimization of the dosing interval, targeting a trough concentration of at least < 2 mg/L but preferably < 0.5–1 mg/L, has proven to reduce nephrotoxicity and is therefore recommended in all patients receiving more than one dose of gentamicin. The usefulness of the daily area under the plasma concentration–time curve for predicting nephrotoxicity should be further investigated. Additionally, more research is needed on the optimal PK/PD targets for efficacy in the clinical situations in which gentamicin is currently used, that is, as monotherapy for urinary tract infections or as part of short-term combination therapy.