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Molecules (Basel, Switzerland) Dec 2017Aminoglycosides are a group of antibiotics used since the 1940s to primarily treat a broad spectrum of bacterial infections. The primary resistance mechanism against... (Review)
Review
Aminoglycosides are a group of antibiotics used since the 1940s to primarily treat a broad spectrum of bacterial infections. The primary resistance mechanism against these antibiotics is enzymatic modification by aminoglycoside-modifying enzymes that are divided into acetyl-transferases, phosphotransferases, and nucleotidyltransferases. To overcome this problem, new semisynthetic aminoglycosides were developed in the 70s. The most widely used semisynthetic aminoglycoside is amikacin, which is refractory to most aminoglycoside modifying enzymes. Amikacin was synthesized by acylation with the l-(-)-γ-amino-α-hydroxybutyryl side chain at the C-1 amino group of the deoxystreptamine moiety of kanamycin A. The main amikacin resistance mechanism found in the clinics is acetylation by the aminoglycoside 6'--acetyltransferase type Ib [AAC(6')-Ib], an enzyme coded for by a gene found in integrons, transposons, plasmids, and chromosomes of Gram-negative bacteria. Numerous efforts are focused on finding strategies to neutralize the action of AAC(6')-Ib and extend the useful life of amikacin. Small molecules as well as complexes ionophore-Zn or Cu were found to inhibit the acetylation reaction and induced phenotypic conversion to susceptibility in bacteria harboring the gene. A new semisynthetic aminoglycoside, plazomicin, is in advance stage of development and will contribute to renewed interest in this kind of antibiotics.
Topics: Amikacin; Anti-Bacterial Agents; Bacterial Infections; Genes, Bacterial; Gram-Negative Bacteria; Humans; Kanamycin Resistance
PubMed: 29257114
DOI: 10.3390/molecules22122267 -
International Journal of Environmental... Feb 2022Children show a very wide range of physical development processes. These changes impact pharmacokinetic (PK) variability in pediatric patients. Most PK studies have been... (Review)
Review
Children show a very wide range of physical development processes. These changes impact pharmacokinetic (PK) variability in pediatric patients. Most PK studies have been conducted on the Caucasian population. Therefore, whether current evidence of how developmental change affects PK and exposure-response relationships applies to Japanese pediatric patients remains unclear. This narrative review focuses on amikacin therapy in Japanese pediatric patients and shows the relationship between amikacin concentrations and efficacy/toxicity. Ten relevant articles were identified. Of these, nine articles were published in the 1980s. All studies reported a maximum concentration (Cmax) and minimum concentration (Cmin) of amikacin. Overall, articles reporting PK/pharmacodynamic (PD) indices and minimum inhibitory concentration (MIC) of isolated bacteria in Japanese pediatric patients is lacking, whereas all patients recovered from an infection state and showed negative cultures. Five of the included studies reported the association between Cmin and toxicity. The Cmin in three of four patients who developed toxicity was above 10 mg/L. This narrative review shows that further PK study of amikacin in Japanese pediatric patients is necessary. In particular, the pursuit of knowledge of Cmax/MIC ratio is vital. On the other hand, this review demonstrates that the optimal Cmin for Japanese pediatric patients is below 10 mg/L as a candidate concentration. However, it is noted that the number of patients who developed toxicity is very small.
Topics: Amikacin; Anti-Bacterial Agents; Bacteria; Child; Humans; Japan; Microbial Sensitivity Tests
PubMed: 35206156
DOI: 10.3390/ijerph19041972 -
The Journal of Antimicrobial... Oct 2016The objectives of this study were to identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures... (Review)
Review
OBJECTIVES
The objectives of this study were to identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures related to nephrotoxicity and ototoxicity.
METHODS
A literature review was conducted in Medline, EMBASE and the Cochrane Central Register of Controlled Trials. Full journal articles reporting randomized controlled trials, controlled clinical trials, interrupted time series trials, and controlled before and after studies involving amikacin therapeutic drug monitoring (TDM) and dose adjustment were considered for inclusion.
RESULTS
Seventeen studies for inclusion were identified, comprising 1677 participants. Amikacin doses ranged from 11 to 15 mg/kg/day with 13 studies using 15 mg/kg/day. Studies were generally designed to compare different aminoglycosides rather than to assess concentration-effect relationships. Only 11 papers presented data on target concentrations, rate of clinical cure and toxicity. Target peak concentrations ranged from 15 to 40 mg/L and target troughs were typically <10 or <5 mg/L. It was not clear whether these targets were achieved. Measured peaks averaged 28 mg/L for twice-daily dosing and 40-45 mg/L for once-daily dosing; troughs averaged 5 and 1-2 mg/L, respectively. Fifteen of the included studies reported rates of nephrotoxicity; auditory and vestibular toxicities were reported in 12 and 8 studies.
CONCLUSIONS
This systematic review found little published evidence to support an optimal dosage regimen or TDM targets for amikacin therapy. The use of alternative approaches, such as consensus opinion and a review of current practice, will be required to develop guidelines to maximize therapeutic outcomes and minimize toxicity with amikacin.
Topics: Adult; Amikacin; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Humans; Interrupted Time Series Analysis; Treatment Outcome
PubMed: 27494904
DOI: 10.1093/jac/dkw250 -
Annals of Internal Medicine Sep 1981
Review
Topics: Amikacin; Ear Diseases; Humans; Kanamycin; Kidney Diseases; Kinetics
PubMed: 7023310
DOI: 10.7326/0003-4819-95-3-328 -
Tuberculosis (Edinburgh, Scotland) Mar 2008
Review
Topics: Amikacin; Animals; Antitubercular Agents; Humans; Mice; Treatment Outcome; Tuberculosis
PubMed: 18486037
DOI: 10.1016/S1472-9792(08)70003-9 -
Clinical Pharmacokinetics Feb 2017Amikacin is an aminoglycoside commonly used in intensive care units for the treatment of patients with life-threatening Gram-negative infections. Although... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Amikacin is an aminoglycoside commonly used in intensive care units for the treatment of patients with life-threatening Gram-negative infections. Although aminoglycosides are extensively used, the accurate determination of their optimal dosage is complicated by marked intra- and interindividual variability in intensive care unit patients. Amikacin pharmacokinetics have been described in numerous studies over the past 25 years.
OBJECTIVE
This review presents a synthesis of the population pharmacokinetic models for amikacin described in critically ill patients. The objective was to determine whether there was a consensus on a structural model and which covariates had been identified.
METHODS
A literature search was conducted from the PubMed database, from its inception up until December 2015, using the following terms: 'amikacin', 'pharmacokinetic(s)', 'population', 'model(ling)' and 'nonlinear mixed effect'. Articles were excluded if they were not pertinent. The reference lists of all selected articles were also evaluated.
RESULTS
Ten articles were included in this review: pharmacokinetics of amikacin were described by a one-compartment or a two-compartment model. Various covariates were tested, but only two (creatinine clearance and total body weight) were included in almost all of the described models. After inclusion of these covariates, the interindividual variability (range) in clearance and the volume of distribution were 44.4 % (28.2-69.4 %) and 31.3 % (8.1-44.7 %), respectively. The residual variability (range) was around 21.0 % (9.0-31.0 %), using a proportional model, and for a combined model (proportional/additive), the median (range) values were 0.615 mg/L (0.2-1.03 mg/L) and 29.2 % (26.8-31.6 %).
CONCLUSION
This review highlights the different population pharmacokinetic models for amikacin developed in critically ill patients over the past decades and proposes relevant information for clinicians and researchers. To optimize amikacin dosage, this review points out the relevant covariates according to the target population. In a population of critically ill patients, dose optimization mainly depends on creatinine clearance and total body weight. New pharmacokinetic population studies could be considered, with new covariates of interest to be tested in model building and to further explain variability. Another future perspective could be external evaluation of previously published models.
Topics: Amikacin; Anti-Bacterial Agents; Clinical Trials as Topic; Critical Illness; Female; Humans; Male
PubMed: 27324191
DOI: 10.1007/s40262-016-0428-x -
Drugs Apr 2019Amikacin liposome inhalation suspension (ALIS; Arikayce) [formerly known as liposomal amikacin for inhalation, or LAI] is a liposomal formulation of the aminoglycoside... (Review)
Review
Amikacin liposome inhalation suspension (ALIS; Arikayce) [formerly known as liposomal amikacin for inhalation, or LAI] is a liposomal formulation of the aminoglycoside antibacterial drug amikacin. The ALIS formulation, administered via inhalation following nebulization, is designed to facilitate targeted and localized drug delivery to the lungs while minimizing systemic exposure. Based on the prespecified primary endpoint analysis of the ongoing phase III CONVERT trial, ALIS has been approved in the USA for use as part of a combination antibacterial drug regimen against Mycobacterium avium complex (MAC) lung disease that is treatment refractory (i.e. an active infection present despite ≥ 6 consecutive months of a multidrug regimen) in adult patients who have limited or no alternative treatment options. In the CONVERT trial, once-daily ALIS as an add-on to guidelines-based therapy (GBT) significantly increased the odds of achieving sputum culture conversion by month 6 compared with GBT alone in patients with treatment-refractory MAC lung disease. The addition of ALIS to GBT was associated with an increased risk of respiratory adverse events compared with GBT alone; however, serious adverse events were experienced by a similar proportion of patients in the two treatment groups. In conclusion, although current evidence for efficacy is limited to microbiological outcomes (with clinical benefit yet to be established), available data suggest that ALIS is a useful option for the treatment of patients with MAC lung disease who have not responded to conventional therapy and for whom there are limited or no alternative treatment options available.
Topics: Administration, Inhalation; Adolescent; Adult; Aged; Aged, 80 and over; Amikacin; Anti-Bacterial Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Delivery Systems; Female; Humans; Liposomes; Lung Diseases; Male; Middle Aged; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Treatment Outcome; Young Adult
PubMed: 30877642
DOI: 10.1007/s40265-019-01095-z -
Therapeutic Drug Monitoring 1985Amikacin, a semisynthetic analog of kanamycin, is very active against most gram-negative bacteria including gentamicin- and tobramycin-resistant strains. The... (Review)
Review
Amikacin, a semisynthetic analog of kanamycin, is very active against most gram-negative bacteria including gentamicin- and tobramycin-resistant strains. The effectiveness of amikacin in the treatment of serious gram-negative bacillary infections is well documented. Due to its resistance to inactivating enzymes, it is the aminoglycoside of choice for the treatment of known or suspected serious gram-negative infections caused by organisms resistant to gentamicin or tobramycin. Amikacin should be part of an empiric antibiotic regimen for the therapy of suspected sepsis in febrile, leukopenic immunocompromised hosts since it exhibits enhanced activity against the organisms most frequently encountered in this patient population. High response rates have been reported with the use of amikacin combined with beta-lactam antibiotics in immunocompromised or granulocytopenic patients. It exhibits impressive in vitro synergy against aminoglycoside-sensitive and -resistant organisms when used in combination with the new acylureidopenicillins and third-generation cephalosporins. Amikacin has the advantage of being the aminoglycoside least inactivated by the semisynthetic penicillins. Amikacin achieves high and predictable serum concentrations and has a favorable therapeutic index. Its potential for nephrotoxicity and ototoxicity is not significantly different than that encountered with gentamicin or tobramycin. Amikacin appears to be the preferred aminoglycoside for use at the present time because of its activity against gentamicin- and tobramycin-resistant organisms, its low resistance potential, its relative low degree of inactivation by the semisynthetic penicillins, and its superior pharmacokinetic profile.
Topics: Amikacin; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Drug Synergism; Humans; Kanamycin; Lactams; Penicillin Resistance; Penicillins
PubMed: 3887667
DOI: 10.1097/00007691-198503000-00003 -
Expert Opinion on Drug Metabolism &... Feb 2017For safe and effective use of antibacterial agents in neonates, specific knowledge on the pharmacokinetics (PK) and its covariates is needed. This necessitates a... (Review)
Review
For safe and effective use of antibacterial agents in neonates, specific knowledge on the pharmacokinetics (PK) and its covariates is needed. This necessitates a stepwise approach, including prospective validation. Areas covered: We describe our approach throughout almost two decades to improve amikacin exposure in neonates. A dosing regimen has been developed and validated using pharmacometrics, considering current weight, postnatal age, perinatal asphyxia, and ibuprofen use. This regimen has been developed based on clinical and therapeutic drug monitoring (TDM) data collected during routine care, and subsequently underwent prospective validation. A similar approach has been scheduled to quantify the impact of hypothermia. Besides plasma observations, datasets on deep compartment PK were also collected. Finally, the available literature on developmental toxicology (hearing, renal) of amikacin is summarized. Expert opinion: The amikacin model reflects a semi-physiological function for glomerular filtration. Consequently, this model can be used to develop dosing regimens for other aminoglycosides or to validate physiology-based pharmacokinetic models. Future studies should explore safety with incorporation of covariates like pharmacogenetics, biomarkers, and long-term outcomes. This includes a search for mechanisms of developmental toxicity. Following knowledge generation and grading the level of evidence in support of data, dissemination and implementation initiatives are needed.
Topics: Amikacin; Animals; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Glomerular Filtration Rate; Humans; Infant, Newborn; Models, Biological
PubMed: 27623706
DOI: 10.1080/17425255.2017.1234606 -
Life Sciences Nov 2021Hypodermic delivery of amikacin is a widely adopted treatment modality for severe infections, including bacterial septicemia, meningitis, intra-abdominal infections,... (Review)
Review
Hypodermic delivery of amikacin is a widely adopted treatment modality for severe infections, including bacterial septicemia, meningitis, intra-abdominal infections, burns, postoperative complications, and urinary tract infections in both paediatric and adult populations. In most instances, the course of treatment requires repeated bolus doses of amikacin, prolonged hospitalization, and the presence of a skilled healthcare worker for administration and continuous therapeutic monitoring to manage the severe adverse effects. Amikacin is hydrophilic and exhibits a short half-life, which further challenges the delivery of sufficient systemic concentrations when administered by the oral or transdermal route. In this purview, the exploitation of novel controlled and sustained release drug delivery platforms is warranted. Furthermore, it has been shown that novel delivery systems are capable of increasing the antibacterial activity of amikacin at lower doses when compared to the conventional formulations and also aid in overcoming the development of drug-resistance, which currently is a significant threat to the healthcare system worldwide. The current review presents a comprehensive overview of the developmental history of amikacin, the mechanism of action in virulent strains as well as the occurrence of resistance, and various emerging drug delivery solutions developed both by the academia and the industry. The examples outlined within the review provides significant pieces of evidence on novel amikacin formulations in the field of antimicrobial research paving the path for future therapeutic interventions that will result in improved clinical outcome.
Topics: Amikacin; Animals; Clinical Trials as Topic; Drug Carriers; Drug Delivery Systems; Drug Liberation; Humans; Nanoparticles
PubMed: 34390724
DOI: 10.1016/j.lfs.2021.119883