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Microbiology Spectrum Aug 2023Amid the mounting burden of multidrug-resistant (MDR) bacterial infections on health care worldwide, drug repurposing, a time and cost-effective strategy to identify new...
Amid the mounting burden of multidrug-resistant (MDR) bacterial infections on health care worldwide, drug repurposing, a time and cost-effective strategy to identify new applications for drugs approved for other indications, can effectively fill the void in the current antibiotic pipeline. In this study, we have repurposed a topical antifungal agent, oxiconazole, in combination with gentamicin against skin infections caused by multidrug-resistant Staphylococcus aureus. Oxiconazole was identified as having antibacterial activity against S. aureus via whole-cell screening assays against clinically relevant bacterial pathogens. It exhibited a potent profile, including equipotent activity against clinical drug-susceptible and -resistant S. aureus and spp. Checkerboard assays and time-kill kinetics studies demonstrated its concentration-dependent killing and ability to synergize with the approved antibiotics daptomycin and gentamicin against susceptible and MDR S. aureus strains. Oxiconazole also significantly eradicated preformed S. aureus biofilms . Eventually, in an assessment of its ability to generate resistant S. aureus mutants via serial passaging, oxiconazole displayed an extremely low propensity for developing stable resistance in S. aureus. Its efficacy alone and in combination with synergistic antibiotics was assessed in a murine superficial skin infection model of S. aureus, where it strongly synergized with gentamicin, exhibiting superior activity to the untreated control and drug-alone treatment groups. Thus, oxiconazole can be repurposed as an antibacterial alone and in combination with gentamicin against susceptible and gentamicin-resistant S. aureus infections. Staphylococcus aureus, which causes the majority of nosocomial and community-acquired infections globally, is a WHO high-priority pathogen for antibiotic research and development. In addition to invasive infections, it is the causative agent of moderate to severe skin infections, with an increasing prevalence of infections caused by MDR strains such as methicillin-resistant S. aureus (MRSA). Our study highlights the repurposing of oxiconazole, a topical antifungal agent, as an ideal candidate for combination therapy with gentamicin against susceptible and drug-resistant S. aureus skin infections due to its extremely low propensity for resistance generation in S. aureus, activity against MDR strains, bactericidal killing kinetics alone and in combination, broad antifungal efficacy, and excellent safety and tolerability profile.
Topics: Humans; Animals; Mice; Methicillin-Resistant Staphylococcus aureus; Staphylococcus aureus; Gentamicins; Antifungal Agents; Microbial Sensitivity Tests; Anti-Bacterial Agents; Staphylococcal Infections
PubMed: 37428033
DOI: 10.1128/spectrum.05031-22 -
Organic Letters May 2020The clinical aminoglycoside antibiotic gentamicin is a mixture of several difficult-to-separate major and minor components. The relative inaccessibility of the minor...
The clinical aminoglycoside antibiotic gentamicin is a mixture of several difficult-to-separate major and minor components. The relative inaccessibility of the minor components in particular complicates efforts to separate antibacterial activity from nephro- and/or ototoxicity and to clarify the origin of the potentially therapeutically important read-through activity. With a view to facilitating such studies, the synthesis of a fully and selectively protected garamine-based acceptor has been developed from readily available sisomicin. Glycosylation of this acceptor with a 6-azido-6,7-dideoxy-d-glycero-d-glucoheptopyranosyl donor affords gentamicin B1 after deprotection, whereas employment of a 2-azido-2-deoxy-d-glucopyranosyl donor under ,-dimethylformamide-directed glycosylation conditions affords gentamicin X2 after deprotection.
Topics: Aminoglycosides; Anti-Bacterial Agents; Disaccharides; Gentamicins; Glycosylation; Humans; Molecular Structure
PubMed: 32343899
DOI: 10.1021/acs.orglett.0c01107 -
Journal of Veterinary Internal Medicine May 2018Therapeutic drug monitoring and minimum inhibitory concentration (MIC) data allow more informed use of gentamicin.
BACKGROUND
Therapeutic drug monitoring and minimum inhibitory concentration (MIC) data allow more informed use of gentamicin.
HYPOTHESIS/OBJECTIVES
To measure peak and trough serum gentamicin concentrations in horses after a 6.6 mg/kg dose of gentamicin given IV and the MIC of gentamicin of bacteria for which gentamicin might be selected.
METHODS
Retrospective analysis of hospital records. Peak and trough plasma gentamicin concentrations were measured after 6.6 mg/kg gentamicin IV in 339 hospitalized horses. The MIC of gentamicin was measured for 503 isolates from ambulatory practice and 33 from hospital practice. The distribution of gentamicin concentrations and MIC results were compared to current recommendations for MIC breakpoints.
RESULTS
The median serum gentamicin concentration at 60 minutes after administration (C ) was 21.4 μg/mL with a distribution indicating that bacteria with MIC ≥2 μg/mL were unlikely to be exposed to sufficient gentamicin for effective killing. Approximately 90% of isolates from ambulatory practice and 36% of hospital isolates had MICs at or below breakpoints for susceptibility with most of the remainder unlikely to be responsive, even to higher IV doses.
CONCLUSIONS AND CLINICAL IMPORTANCE
Gentamicin at a dosage of 6.6 mg/kg IV is likely to be effective against the majority of infections encountered in ambulatory practice, but less effective in an equine hospital. Because there was a dichotomy of most bacteria as being clearly susceptible or clearly resistant to gentamicin, it appears unlikely that higher doses would have been more efficacious, especially in the hospitalized population in our study.
Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Gentamicins; Horse Diseases; Horses; Microbial Sensitivity Tests; Retrospective Studies
PubMed: 29575239
DOI: 10.1111/jvim.15078 -
Clinical Obstetrics and Gynecology Sep 2008Gentamicin, an aminoglycoside with broad antimicrobial activity, is commonly used in both obstetrics and gynecology. Traditional dosing regimens for gentamicin have... (Review)
Review
Gentamicin, an aminoglycoside with broad antimicrobial activity, is commonly used in both obstetrics and gynecology. Traditional dosing regimens for gentamicin have called for 3 times daily dosing, but recent insights into the pharmacodynamics of the drug have led to multiple studies of once-daily dosing regimens. Many studies have demonstrated efficacy, safety, and economy of the 24-hour dosing interval, resulting in recommendations that this become the standard for aminoglycoside administration. However, because of the unique considerations for drug administration in pregnant and postpartum women, the once-daily dosing regimens have not been widely adopted. Additional studies in pregnant and postpartum women have demonstrated therapeutic noninferiority, no increase in adverse events, and significant cost savings with once-daily dosing versus 3 times daily dosing of gentamicin. We review the literature and present rationale based on multiple controlled studies supporting single-daily dosing of gentamicin, 5 mg/kg/d actual body weight, for many common obstetrics-gynecology infections.
Topics: Adult; Anti-Bacterial Agents; Chorioamnionitis; Dose-Response Relationship, Drug; Drug Administration Schedule; Endometritis; Female; Gentamicins; Humans; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Puerperal Disorders; Safety; Treatment Outcome
PubMed: 18677142
DOI: 10.1097/GRF.0b013e31818091cd -
The Journal of Antimicrobial... Feb 2022This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis. (Clinical Trial)
Clinical Trial
OBJECTIVES
This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis.
METHODS
Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens.
RESULTS
A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine.Simulation-based PKPD assessments suggest good Gram-positive (MIC ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index < 0.5 (synergy) and most in the range 0.5-1 (suggesting additivity). Simulations showed that feasible dosing strategies would be insufficient to cover resistant strains.
CONCLUSIONS
PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis.
Topics: Ampicillin; Anti-Bacterial Agents; Escherichia coli; Gentamicins; Humans; Infant, Newborn; Neonatal Sepsis; Sepsis
PubMed: 35107141
DOI: 10.1093/jac/dkab413 -
JAMA Dermatology Apr 2022Junctional epidermolysis bullosa (JEB) is an incurable blistering skin disorder with high infant mortality often caused by nonsense variants in the genes that encode... (Clinical Trial)
Clinical Trial
IMPORTANCE
Junctional epidermolysis bullosa (JEB) is an incurable blistering skin disorder with high infant mortality often caused by nonsense variants in the genes that encode laminin 332.
OBJECTIVE
To evaluate the safety and outcomes following intravenous gentamicin readthrough therapy and subsequent laminin 332 expression in patients with JEB.
DESIGN, SETTING, AND PARTICIPANTS
This open-label, pilot nonrandomized clinical trial assessed 1 course of low- or high-dose intravenous gentamicin, including follow-up at 30 and 90 days after treatment. Five pediatric patients with JEB (2 with intermediate JEB and 3 with severe JEB) and confirmed nonsense variants in LAMA3 or LAMB3 in 1 or 2 alleles and decreased expression of laminin 332 at the dermal-epidermal junction of their skin participated in the study, which was performed at a single institution in collaboration with physicians and home infusion services near the patients from April 1, 2019, to February 28, 2021, with follow-up until May 31, 2021.
INTERVENTIONS
Three patients received gentamicin at 7.5 mg/kg daily for 14 days, and 2 patients received gentamicin at 10 mg/kg daily for 24 days.
MAIN OUTCOMES AND MEASURES
Primary outcomes were change in expression of laminin 332 in patients' skin and assessments for safety (ototoxic effects, nephrotoxic effects, and autoimmune response). Secondary outcomes included wound healing in monitored wounds and Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) score.
RESULTS
After gentamicin treatment, all 5 patients (age range, 3 months to 10 years, 4 [80%] female) exhibited increased laminin 332 in the dermal-epidermal junction. By 1 month, 7 of 9 wounds in patients receiving low-dose intravenous gentamicin and all wounds in patients receiving high-dose intravenous gentamicin exhibited at least 50% wound closure. By 3 months, 8 of 9 wounds in patients receiving low-dose gentamicin and all wounds in patients receiving high-dose intravenous gentamicin exhibited greater than 85% closure. All 3 patients who were evaluated with EBDASI showed a decrease in total activity scores that met minimal clinically important differences 1 month after treatment. All 5 patients completed the study, and no ototoxic effects, nephrotoxic effects, or anti-laminin 332 antibodies were detected.
CONCLUSIONS AND RELEVANCE
In this nonrandomized clinical trial, intravenous gentamicin therapy was associated with induced readthrough of nonsense variants in patients with JEB, restored functional laminin 332 in their skin, and wound closure during the 3-month study period. Although long-term safety and efficacy requires further evaluation, a single cycle of intravenous gentamicin may be a safe and readily available therapy in the short term for this population of patients with JEB.
TRIAL REGISTRATION
ClinicalTrials.gov Identifiers: NCT03526159 and NCT04140786.
Topics: Alleles; Child; Epidermolysis Bullosa, Junctional; Female; Gentamicins; Humans; Infant; Laminin; Male; Skin; Wound Healing
PubMed: 35234826
DOI: 10.1001/jamadermatol.2021.5992 -
Drug Design, Development and Therapy 2022Appropriate gentamicin dosing in continuous renal replacement therapy (CRRT) patients remains undefined. This study aimed to develop a population pharmacokinetic (PK)...
PURPOSE
Appropriate gentamicin dosing in continuous renal replacement therapy (CRRT) patients remains undefined. This study aimed to develop a population pharmacokinetic (PK) model of gentamicin in CRRT patients and to infer the optimal dosing regimen for gentamicin.
METHODS
Fourteen CRRT patients dosed with gentamicin were included to establish a population PK model to characterize the variabilities and influential covariates of gentamicin. The pharmacokinetic/pharmacodynamic (PK/PD) target attainment and risk of toxicity for different combinations of gentamicin regimens (3-7 mg/kg q24h) and CRRT effluent doses (30-50 mL/h/kg) were evaluated by Monte Carlo simulation. The probability of target attainment (PTA) was determined for the PK/PD indices of the ratio of drug peak concentration/minimum inhibitory concentration (C/MIC > 10) and the ratio of area under the drug concentration-time curve/MIC over 24 h (AUC/MIC > 100), and the risk of toxicity was estimated by drug trough concentration thresholds (1 and 2 mg/L).
RESULTS
A one-compartment model adequately described the PK characteristics of gentamicin. Covariates including body weight, age, gender, and CRRT modality did not influence the PK parameters of gentamicin based on our dataset. All studied gentamicin regimens failed to achieve satisfactory PTAs for pathogens with an MIC ≥2 mg/L. A good balance of PK/PD target attainment and risk of toxicity (>2 mg/L) was achieved under 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose for an MIC ≤1 mg/L. CRRT dose intensity had a significant impact on the target attainment of AUC/MIC >100 and risk of toxicity.
CONCLUSION
A combination of 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose might be considered as a starting treatment option for CRRT patients, and drug monitoring is required to manage toxicity.
Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Continuous Renal Replacement Therapy; Critical Illness; Female; Gentamicins; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method
PubMed: 35023902
DOI: 10.2147/DDDT.S343385 -
International Journal of Nanomedicine 2017We investigated the efficacy of liposomal gentamicin formulations of different surface charges against and . The liposomal gentamicin formulations were prepared by the...
We investigated the efficacy of liposomal gentamicin formulations of different surface charges against and . The liposomal gentamicin formulations were prepared by the dehydration-rehydration method, and their sizes and zeta potential were measured. Gentamicin encapsulation efficiency inside the liposomal formulations was determined by microbiologic assay, and stability of the formulations in biologic fluid was evaluated for a period of 48 h. The minimum inhibitory concentration and the minimum bactericidal concentration were determined, and the in vitro time kill studies of the free form of gentamicin and liposomal gentamicin formulations were performed. The activities of liposomal gentamicin in preventing and reducing biofilm-forming and were compared to those of free antibiotic. The sizes of the liposomal formulations ranged from 625 to 806.6 nm in diameter, with the zeta potential ranging from -0.22 to -31.7 mV. Gentamicin encapsulation efficiency inside the liposomal formulation ranged from 1.8% to 43.6%. The liposomes retained >60% of their gentamicin content during the 48 h time period. The minimum inhibitory concentration of neutral formulation was lower than that of free gentamicin (0.25 versus 1 mg/L for and 0.5 versus 1 mg/L for ). The negatively charged formulation exhibited the same bacteriostatic concentration as that of free gentamicin. The minimum bactericidal concentration of neutral liposomes on planktonic bacterial culture was twofold lower than that of free gentamicin, whereas the negatively charged formulations were comparable to free gentamicin. The killing time curve values for the neutral negatively charged formulation against planktonic and were better than those of free gentamicin. Furthermore, liposomal formulations prevent the biofilm-formation ability of these strains better than free gentamicin. In summary, liposomal formulations could be an effective lipid nanoparticle to combat acute infections where planktonic bacteria are predominant.
Topics: Animals; Anti-Bacterial Agents; Biofilms; Gentamicins; Humans; Klebsiella oxytoca; Liposomes; Male; Microbial Sensitivity Tests; Nanoparticles; Particle Size; Plankton; Pseudomonas aeruginosa; Rats
PubMed: 29075113
DOI: 10.2147/IJN.S141709 -
Clinical Infectious Diseases : An... Nov 2020Centers for Disease Control and Prevention (CDC) guidelines recommend 240 mg gentamicin plus 2 g azithromycin for the treatment of gonorrhea in cephalosporin-allergic...
BACKGROUND
Centers for Disease Control and Prevention (CDC) guidelines recommend 240 mg gentamicin plus 2 g azithromycin for the treatment of gonorrhea in cephalosporin-allergic patients. The efficacy of gentamicin alone in the treatment of pharyngeal gonorrhea is uncertain.
METHODS
Between September 2018 and March 2019, we enrolled men who have sex with men with nucleic acid amplification test-diagnosed pharyngeal gonorrhea in a single-arm, unblinded clinical trial. Men received a single 360-mg intramuscular dose of gentamicin and underwent test of cure by culture 4-7 days later. The study measured creatinine at enrollment and test of cure, serum gentamicin concentration postdose to establish peak concentration (Cmax), and standard antimicrobial minimum inhibitory concentrations (MICs) by agar dilution. The trial was designed to establish a point estimate for gentamicin's efficacy for pharyngeal gonorrhea. We planned to enroll 50 evaluable participants; assuming gentamicin was 80% efficacious, the trial would establish a 95% confidence interval (CI) of 66%-90%. We planned interim analyses at n = 10 and n = 25.
RESULTS
The study was stopped early due to poor efficacy. Of 13 enrolled men, 10 were evaluable, and only 2 (20% [95% CI, 2.5%-55.6%]) were cured. Efficacy was not associated with gentamicin Cmax or MIC. No participants experienced renal insufficiency. The mean creatinine percentage change was +5.2% (range, -6.7% to 21.3%). Six (46%) participants experienced headache, all deemed unrelated to treatment.
CONCLUSIONS
Gentamicin alone failed to eradicate Neisseria gonorrhoeae from the pharynx. Clinicians should use caution when treating gonorrhea with the CDC's current alternative regimen (gentamicin 240 mg plus azithromycin 2 g) given increases in azithromycin resistance and gentamicin's poor efficacy at the pharynx.
CLINICAL TRIALS REGISTRATION
NCT03632109.
Topics: Anti-Bacterial Agents; Azithromycin; Gentamicins; Gonorrhea; Homosexuality, Male; Humans; Male; Microbial Sensitivity Tests; Neisseria gonorrhoeae; Pharynx; Sexual and Gender Minorities
PubMed: 31712813
DOI: 10.1093/cid/ciz1109 -
Systematic Reviews Sep 2014A high level of resistance in Neisseria gonorrhoeae has developed against penicillins, sulphonamides, tetracyclines and quinolones, and recent surveillance data have... (Review)
Review
BACKGROUND
A high level of resistance in Neisseria gonorrhoeae has developed against penicillins, sulphonamides, tetracyclines and quinolones, and recent surveillance data have shown a gradual reduction in sensitivity to current first-line agents with an upward drift in the minimum inhibitory concentration of ceftriaxone. Laboratory sensitivity testing suggests that gentamicin, an aminoglycoside, may be an effective treatment option for gonorrhoea infection when used as a single intramuscular dose.
METHODS
A search of electronic reference databases and grey literature was used to identify randomised trials and well-conducted prospective studies with concurrent controls evaluating single-dose gentamicin against placebo or a comparator regimen in the treatment of uncomplicated gonorrhoea infection in men and women aged 16 years and over. The primary outcome was microbiological cure of N. gonorrhoeae.
RESULTS
Eight hundred and thirty-nine studies were identified, of which five (1,063 total participants) were included. All five studies administered single-dose gentamicin via intramuscular injection to men with uncomplicated gonococcal urethritis. Three studies were randomised trials, one was quasi-randomised and one was non-randomised but included a comparator arm. Comparator antibiotics included an alternative aminoglycoside or antibiotic used in the syndromic management of male urethritis. Methodology was poorly described in all five included studies. The high risk of bias within studies and clinical heterogeneity between studies meant that it was inappropriate to pool data for meta-analysis. Cure rates of 62% to 98% were reported with gentamicin treatment. The relative risk of cure was comparable between gentamicin and comparator antibiotics.
CONCLUSIONS
The studies identified provide insufficient data to support or refute the efficacy and safety of single-dose intramuscular gentamicin in the treatment of uncomplicated gonorrhoea infection. Additional randomised trials to evaluate gentamicin for this indication are therefore required.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42012002490.
Topics: Anti-Bacterial Agents; Gentamicins; Gonorrhea; Humans; Injections, Intramuscular; Neisseria gonorrhoeae; Treatment Outcome
PubMed: 25239090
DOI: 10.1186/2046-4053-3-104