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Microbiology Spectrum Jun 2022The emergence of Mycobacterium abscessus complex (MABC) infection is the most noteworthy health care problem. Clarithromycin (CLA) and amikacin (AMK) constitute the...
The emergence of Mycobacterium abscessus complex (MABC) infection is the most noteworthy health care problem. Clarithromycin (CLA) and amikacin (AMK) constitute the cornerstone of treatment for patients infected with MABC; thus, early detection of resistance to these two drugs is essential for formulating effective therapeutic regimens. In the present study, we aimed to validate the use of MeltPro MAB assay, a melting curve analysis with dually labeled probes, on a set of clinical isolates to detect CLA and AMK resistance. A total of 103 clinical MABC strains were collected in our analysis, including 76 strains of M. abscessus . (MAA) and 27 strains of M. abscessus (MAM). susceptibility testing revealed that two isolates exhibited intrinsic CLA resistance by harboring A2270T mutation in , and inducible resistance was noted in 42 isolates. Additionally, two MAA isolates with erm(41)T28 genotype were susceptible to CLA. Notably, we found three out of 44 isolates had two melting curve peaks, representing the simultaneous presence of mutant and the wild type in these specimens. In contrast, no known mutations were identified in six AMK-resistant isolates. Further analysis revealed that MeltPro yielded 100% and 96.67% sensitivity and specificity for detecting CLA resistance. In summary, this study firstly demonstrates that MeltPro is a promising diagnostic for early detection of CLA resistance for MABC isolates, which significantly improves the turnaround time within 2 h. Approximate two fifths of MABC isolates are resistant to CLA by 23S rRNA mutation or its methylation, emphasizing the urgent need for early detection of CLA resistance prior to empirical treatment of MABC infections. Mycobacterium abscessus complex (MABC) has attracted increasing attention due to the numerous cases of infection. This pathogen is notorious for its intrinsic drug resistance, which complicates clinical management of patients with MABC infections. Clarithromycin (CLA) and amikacin (AMK) are the cornerstone of treatment regimens for MABC. Herein, our data firstly demonstrates that MeltPro is a promising diagnostic for early detection of CLA resistance for MABC isolates. The high frequency of CLA-resistant MABC isolates in China emphasizes the urgent need for early detection of CLA resistance prior to empirical treatment of MABC infections.
Topics: Amikacin; Anti-Bacterial Agents; Clarithromycin; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus
PubMed: 35638787
DOI: 10.1128/spectrum.00574-22 -
American Journal of Health-system... Apr 2011The impact of clinical decision support (CDS) on initial doses and intervals and pharmacokinetic outcomes of amikacin and tobramycin therapy was evaluated. (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
The impact of clinical decision support (CDS) on initial doses and intervals and pharmacokinetic outcomes of amikacin and tobramycin therapy was evaluated.
METHODS
A complex CDS advisor to provide guidance on initial dosing and monitoring of aminoglycoside orders, using both traditional-dosing and extended-interval-dosing strategies, was integrated into a computerized prescriber-order-entry (CPOE) system and compared with a control group whose aminoglycoside orders were closely monitored by pharmacists. The primary outcome measured was an initial dose within 10% of a dose calculated to be adherent to published dose guidelines. Secondary outcomes included a guideline-adherent interval, trough and peak concentrations in goal range, and rate of nephrotoxicity.
RESULTS
Of 216 patients studied, 97 were prescribed amikacin and 119 were prescribed tobramycin. The number of orders with initial doses consistent with reference standards increased from 40% in the preadvisor group to 80% in the postadvisor group (p < 0.001). Selection of the correct initial interval based on renal function increased from 63% to 87% (p < 0.001). The changes in the initial dosing and interval resulted in an increase of trough concentrations at goal (59% in the preadvisor group versus 89% in the postadvisor group, p = 0.0004). There was no significant difference in peak concentrations in the goal range or rate of nephrotoxicity.
CONCLUSION
An advisor for aminoglycoside dosing and monitoring integrated into a CPOE system significantly improved selection of initial doses and intervals and resulted in an improvement in the rate of trough serum drug concentrations at goal compared with standard provider dosing.
Topics: Adult; Aged; Amikacin; Decision Support Systems, Clinical; Drug Monitoring; Female; Humans; Male; Middle Aged; Prospective Studies; Tobramycin
PubMed: 21411805
DOI: 10.2146/ajhp100155 -
Journal of Global Antimicrobial... Sep 2022To report reference method antimicrobial susceptibility testing results for recent clinical isolates of Gram-negative bacilli from Morocco.
OBJECTIVES
To report reference method antimicrobial susceptibility testing results for recent clinical isolates of Gram-negative bacilli from Morocco.
METHODS
CLSI (Clinical and Laboratory Standards Institute) broth microdilution antimicrobial susceptibility testing was performed by a central laboratory for isolates of Enterobacterales (n = 810), Pseudomonas aeruginosa (n = 321), and Acinetobacter baumannii (n = 191) collected in 2018-2020 by three hospital laboratories in Morocco. MICs were interpreted using both CLSI (2021) and EUCAST (European Committee on Antimicrobial Susceptibility Testing) (2021) breakpoints. Molecular testing for β-lactamase genes was performed on isolates meeting defined screening criteria.
RESULTS
Most isolates of Enterobacterales were susceptible (CLSI/EUCAST breakpoints) to amikacin (98.0%/96.2%), ceftazidime-avibactam (94.8%/94.8%), and meropenem (92.5%/94.2%). Of Enterobacterales isolates eligible for β-lactamase gene screening (n = 210), 174 were ESBL-positive, 40 were metallo-β-lactamase-positive (all NDM), 39 were serine carbapenemase-positive (all OXA); and 7 isolates carried both OXA-48 and NDM-1. Amikacin (89.1%/89.1%) and ceftazidime-avibactam (88.2%/88.2%) were the most active agents tested against P. aeruginosa. Applying CLSI and EUCAST breakpoints, MDR rates were 21.9% and 29.3% for Enterobacterales and 18.4% and 21.8% for P. aeruginosa. Susceptible rates for amikacin, ceftazidime-avibactam, and meropenem were 93.2%/89.5%, 77.4%/82.3%, and 67.8%/80.2% for MDR Enterobacterales and 50.8%/57.1%, 40.7%/45.7%, and 27.1/32.9% for MDR P. aeruginosa. ≥70% of A. baumannii isolates were resistant to all agents tested (except colistin, EUCAST breakpoints only) including amikacin and meropenem.
CONCLUSION
Newer β-lactam/β-lactamase inhibitor combinations such as ceftazidime-avibactam warrant testing and reporting for Enterobacterales and P. aeruginosa in Morocco given the presence of significant resistance to first-line β-lactams and fluoroquinolones, pervasive ESBLs and carbapenemases, and toxicity concerns associated with some second-line agents.
Topics: Amikacin; Anti-Bacterial Agents; Gram-Negative Bacteria; Meropenem; Morocco; Pseudomonas aeruginosa; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 35447385
DOI: 10.1016/j.jgar.2022.04.011 -
BMC Pharmacology & Toxicology Jun 2019Treatment guidelines suggest either a low-dose or high-dose approach when prescribing amikacin for nontuberculous mycobacterial pulmonary disease (NTM PD), but data...
BACKGROUND
Treatment guidelines suggest either a low-dose or high-dose approach when prescribing amikacin for nontuberculous mycobacterial pulmonary disease (NTM PD), but data supporting the low-dose approach are limited. The purpose of this study was to describe the safety and efficacy of the use of a low-dose of intravenous amikacin in a cohort of patients with NTM PD.
METHODS
We retrospectively reviewed all patients with NTM PD who received amikacin at our institution between July 1, 2003 and February 28, 2017. Demographics, clinical, microbiological and radiological data, indication and dose of amikacin, and adverse drug effects were recorded.
RESULTS
A total of 107 patients received a regimen containing amikacin for a median (IQR) of 7 (4-11) months. Seventy (65.4%) were female and the mean age (SD) was 58.3 (14.9) years. Amikacin was started at a median dose of 9.9 (2.5) mg/kg/day. Ototoxicity was observed in 30/77 (39%) patients and it was related to female sex (OR 4.96, 95%CI 1.24-19.87), and total dose of amikacin per bodyweight (OR 1.62, 95%CI 1.08-2.43). Patients of East Asian ethnicity were less likely to develop ototoxicity (0.24, 95%CI 0.06-0.95). Out of 96 patients who received amikacin for more than 3 months, 65 (67.7%) experienced symptom improvement and 30/62 (49.2%) converted their sputum to culture negative within a year.
CONCLUSIONS
Patients with NTM PD treated with low-dose intravenous amikacin frequently developed ototoxicity, which was associated with female sex, and total dose of amikacin per bodyweight. Physicians should carefully consider dose, treatment duration, and long term prognosis in balancing risks and benefits of intravenous amikacin in NTM PD.
Topics: Administration, Intravenous; Adult; Aged; Amikacin; Anti-Bacterial Agents; Female; Humans; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Ontario; Ototoxicity; Retrospective Studies; Sputum; Treatment Outcome
PubMed: 31159865
DOI: 10.1186/s40360-019-0302-1 -
European Journal of Hospital Pharmacy :... Mar 2022Amikacin is still a widely used aminoglycoside for the treatment of life-threatening infections. The pharmacokinetic parameters of this antibiotic may be altered in...
OBJECTIVES
Amikacin is still a widely used aminoglycoside for the treatment of life-threatening infections. The pharmacokinetic parameters of this antibiotic may be altered in critically ill conditions. Moreover, in the elderly population, pathophysiological changes affect these pharmacokinetic variables, making it difficult to predict the appropriate dose and dosing schedule for amikacin. This study aimed to characterise the pharmacokinetics of amikacin in critically ill elderly patients with renal dysfunction, and to evaluate if the available dose adjustment schedules dependent on renal function would be appropriate for empirical dosing.
METHODS
Critically ill patients aged >60 years with a creatinine clearance of >20 mL/min in need of treatment with amikacin were randomly enrolled. All the patients received approximately 25 mg/kg amikacin. The patients were then divided into three groups according to the stages of their renal dysfunction based on creatinine clearance, and the optimum time to re-dosing was calculated for each group. The pharmacokinetic parameters of the patients were calculated and estimated as population pharmacokinetic data.
RESULTS
Of 30 patients, only 20% attained the target peak levels of amikacin of >64 mg/L. In addition, the mean volume of distribution was 0.47 L/kg. There was a poor correlation between amikacin clearance and creatinine clearance. The difference in amikacin half-life was not statistically significant among any of the stages of renal impairment.
CONCLUSIONS
The initial dosing of amikacin in critically ill elderly patients should not be reduced, even in the context of renal impairment. Regarding the dose adjustment in renal impairment, dosing intervals estimation, no decision can be made based on the creatinine clearance and the first dose individualisation method in terms of the two-sample measurements may be considered as an appropriate strategy.
Topics: Aged; Amikacin; Anti-Bacterial Agents; Critical Illness; Half-Life; Humans; Kidney Diseases; Middle Aged
PubMed: 34588225
DOI: 10.1136/ejhpharm-2021-002986 -
Antimicrobial Agents and Chemotherapy Sep 2017The prolonged use of injectable agents in a regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) is recommended by the World Health Organization,...
The prolonged use of injectable agents in a regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) is recommended by the World Health Organization, despite its association with ototoxicity and nephrotoxicity. We undertook this study to look at the relative adverse effects of capreomycin and amikacin. We reviewed the case notes of 100 consecutive patients treated at four MDR-TB treatment centers in the United Kingdom. The median total duration of treatment with an injectable agent was 178 days (interquartile range [IQR], 109 to 192 days; = 73) for those with MDR-TB, 179 days (IQR, 104 to 192 days; = 12) for those with MDR-TB plus fluoroquinolone resistance, and 558 days (IQR, 324 to 735 days; = 8) for those with extensively drug-resistant tuberculosis (XDR-TB). Injectable use was longer for those started with capreomycin (183 days; IQR, 123 to 197 days) than those started with amikacin (119 days; IQR, 83 to 177 days) ( = 0.002). Excluding patients with XDR-TB, 51 of 85 (60%) patients were treated with an injectable for over 6 months and 12 of 85 (14%) were treated with an injectable for over 8 months. Forty percent of all patients discontinued the injectable due to hearing loss. Fifty-five percent of patients experienced ototoxicity, which was 5 times (hazard ratio [HR], 5.2; 95% confidence interval [CI], 1.2 to 22.6; = 0.03) more likely to occur in those started on amikacin than in those treated with capreomycin only. Amikacin was associated with less hypokalemia than capreomycin (odds ratio, 0.28; 95% CI, 0.11 to 0.72), with 5 of 37 (14%) patients stopping capreomycin due to recurrent electrolyte loss. There was no difference in the number of patients experiencing a rise in the creatinine level of >1.5 times the baseline level. Hearing loss is frequent in this cohort, though its incidence is significantly lower in those starting capreomycin, which should be given greater consideration as a first-line agent.
Topics: Acute Kidney Injury; Adult; Amikacin; Antitubercular Agents; Capreomycin; Drug Therapy, Combination; Female; Hearing Loss; Humans; Hypokalemia; Male; Mycobacterium tuberculosis; Retrospective Studies; Tuberculosis, Multidrug-Resistant; Young Adult
PubMed: 28696239
DOI: 10.1128/AAC.02586-16 -
Antimicrobial Agents and Chemotherapy Jan 2017There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A...
Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy.
There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 10 CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid amplification of resistant P. aeruginosa strains (about 10 to 10 CFU/ml within 24 to 48 h). For K. pneumoniae, amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates.
Topics: Aerosols; Amikacin; Anti-Bacterial Agents; Colony Count, Microbial; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Fosfomycin; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Models, Biological; Pseudomonas aeruginosa; Respiratory Mucosa
PubMed: 27795380
DOI: 10.1128/AAC.01763-16 -
Microbiology Spectrum Oct 2022Pseudomonas aeruginosa (PA) biofilm infection is clinically prevalent and difficult to eradicate. In the present work, we aimed to evaluate the and efficacy of...
Pseudomonas aeruginosa (PA) biofilm infection is clinically prevalent and difficult to eradicate. In the present work, we aimed to evaluate the and efficacy of colistin (COL)-based combinations against PA biofilm. MICs and fractional inhibitory concentration indexes (FICIs) of four antibiotics (COL, amikacin, levofloxacin, and meropenem) to bioluminescent strain PAO1, carbapenem-resistant PAO1 (CRPAO1), and clinically isolated strains were assessed. Minimal biofilm eradication concentrations (MBECs) of monotherapy and combinations were examined by counting the live bacteria in biofilm, accompanied by visual confirmation using confocal laser-scanning microscopy. An animal biofilm infection model was established by implanting biofilm subcutaneously, and the therapeutic effect was evaluated according to the change in luminescence through a live animal bio-photonic imaging system. , even combined with 4 or 8 mg/L COL, meropenem needed to reach 128 or 256 mg/L to eradicate the biofilm. Moreover, 2 mg/L COL combined with 32 mg/L amikacin or 4-8 mg/L levofloxacin could kill the PAO1 and CRPAO1 in biofilm within 24 h. , COL combined with amikacin or levofloxacin could shorten the eradication time of biofilm than monotherapy. For PAO1 biofilm, combination therapy could eradicate the biofilm in all mice on the 5th day, whereas monotherapy only eradicated biofilms in almost half of the mice. For CRPAO1 biofilm, the biofilm eradication rate on the 6th day in the COL+ amikacin, amikacin, or COL alone regimen was 90%, 10%, or 40%, respectively. COL combined with levofloxacin did not show a better effect than each individual antibiotic. COL-based combinations containing levofloxacin or amikacin were promising choices for treating PA biofilm infection. Infections associated with PA biofilm formation are extremely challenging. When monotherapy fails to achieve optimal efficacy, combination therapy becomes the last option. After evaluating multiple drug combinations through a series of experiments and , we confirmed that colistin-based combinations containing levofloxacin or amikacin were promising choices for treating PA biofilm infection. The efficacy of these combinations derives from the different bactericidal mechanisms and the bacterial susceptibility to each antibiotic. This study provided a new regimen to solve the incurable problem of biofilm by using COL combined with other antibiotics.
Topics: Mice; Animals; Colistin; Amikacin; Levofloxacin; Pseudomonas aeruginosa; Meropenem; Drug Resistance, Multiple, Bacterial; Pseudomonas Infections; Biofilms; Anti-Bacterial Agents; Microbial Sensitivity Tests; Carbapenems; Drug Combinations
PubMed: 36102678
DOI: 10.1128/spectrum.01468-22 -
Antimicrobial Agents and Chemotherapy Aug 2020Despite excellent activity, aminoglycosides are used conservatively to treat multidrug-resistant bacterial infections due to their associated nephrotoxicity....
Despite excellent activity, aminoglycosides are used conservatively to treat multidrug-resistant bacterial infections due to their associated nephrotoxicity. Aminoglycosides are known to accumulate in the kidneys, but the quantitative relationship between drug exposures and nephrotoxicity is not well established. To bridge the knowledge gap, the objective of this study was to develop an animal model with clinically relevant conditions to mimic human disease progression. Single-dose pharmacokinetics were studied in Sprague-Dawley rats dosed either with 100 or 500 mg/kg of body weight of amikacin subcutaneously. Serial blood samples were collected, and serum amikacin concentrations were measured using liquid chromatography tandem mass spectrometry. Rats were also dosed with amikacin once daily for up to 10 days; blood samples were taken at baseline and daily to detect nephrotoxicity (defined as doubling of serum creatinine from baseline). Kidneys from both studies were harvested from selected rats, and amikacin concentrations in renal tissues were measured. A dose-dependent increase in systemic area under the curve (AUC) was observed, which ranged from approximately 1/3 (AUC of 53 mg·h/liter) to 3 times (AUC of 650 mg·h/liter) the expected exposure resulting from standard dosing in humans. Nephrotoxicity was significantly higher in rats given 500 mg/kg (100% versus 30%, 0.003). Kaplan-Meier analysis also showed a significant difference in nephrotoxicity onset between the two groups (0.001). Finally, analysis of the renal tissues showed that the accumulation of amikacin could be associated with nephrotoxicity. These results are consistent with clinical observations, which support using this model in the future to investigate an intervention(s) that can be used clinically to alleviate nephrotoxicity.
Topics: Amikacin; Aminoglycosides; Animals; Anti-Bacterial Agents; Disease Models, Animal; Pharmaceutical Preparations; Rats; Rats, Sprague-Dawley
PubMed: 32571819
DOI: 10.1128/AAC.00859-20 -
PloS One 2023Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as...
BACKGROUND
Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of individual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates.
METHODS
We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with individual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model.
RESULTS
Among 242 patients, 131 (54%) were male, 97 (40%) were living with HIV, 175 (72%) received second-line treatment prior to first hospitalization, and 191 (79%) died during the study period. At initial hospitalization, 134 (55%) patients had Mycobacterium tuberculosis with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42%) had resistance to ofloxacin and/or amikacin. Most patients (129 [53%]) had multiple hospitalizations and DST changes occurred in 146 (60%) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18%), capreomycin (18%), PAS (17%) and kanamycin (16%) than other DR-TB drugs (P<0.001), including ethionamide (8%), moxifloxacin (7%), terizidone (7%), ethambutol (7%), and pyrazinamide (6%). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56-1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51-0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations.
CONCLUSION
We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed.
Topics: Adult; Humans; Male; Female; Antitubercular Agents; Retrospective Studies; Ethionamide; South Africa; Amikacin; Tuberculosis, Multidrug-Resistant; Mycobacterium tuberculosis; Aminosalicylic Acid; Ofloxacin; HIV Infections; Hospitals; Microbial Sensitivity Tests
PubMed: 36780443
DOI: 10.1371/journal.pone.0281097