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The Journal of Antimicrobial... Nov 2022Annual mortality from neonatal sepsis is an estimated 430 000-680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO...
BACKGROUND
Annual mortality from neonatal sepsis is an estimated 430 000-680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO currently recommends a narrow-spectrum β-lactam (e.g. ampicillin) and gentamicin as first-line empirical therapy. However, available epidemiological data demonstrate high rates of resistance to both agents. Alternative empirical regimens are needed. Flomoxef and amikacin are two off-patent antibiotics with potential for use in this setting.
OBJECTIVES
To assess the pharmacodynamics of flomoxef and amikacin in combination.
METHODS
The pharmacodynamic interaction of flomoxef and amikacin was assessed in chequerboard assays and a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment. The combination was further assessed in HFIM experiments mimicking neonatal plasma exposures of clinically relevant doses of both drugs against five Enterobacterales isolates with a range of flomoxef/amikacin MICs.
RESULTS
Flomoxef and amikacin in combination were synergistic in bacterial killing in both assays and prevention of emergence of amikacin resistance in the HFIM. In the HFIM assessing neonatal-like drug exposures, the combination killed 3/5 strains to sterility, (including 2/5 that monotherapy with either drug failed to kill) and failed to kill the 2/5 strains with flomoxef MICs of 32 mg/L.
CONCLUSIONS
We conclude that the combination of flomoxef and amikacin is synergistic and is a potentially clinically effective regimen for the empirical treatment of neonatal sepsis in LMIC settings and is therefore suitable for further assessment in a clinical trial.
Topics: Infant; Infant, Newborn; Humans; Amikacin; Neonatal Sepsis; Cephalosporins; Microbial Sensitivity Tests; Anti-Bacterial Agents; Delivery of Health Care
PubMed: 36177766
DOI: 10.1093/jac/dkac323 -
Microbiology Spectrum Apr 2022Relebactam is a novel β-lactamase inhibitor of Ambler class A and C β-lactamases that has been developed in combination with imipenem/cilastatin for the treatment of...
Relebactam is a novel β-lactamase inhibitor of Ambler class A and C β-lactamases that has been developed in combination with imipenem/cilastatin for the treatment of carbapenem-resistant bacterial infections. In this study, we evaluated the antibacterial activity of imipenem/relebactam (IMR) against imipenem-nonsusceptible Enterobacterales and Pseudomonas aeruginosa isolates from Japan. Two sets of antibacterial susceptibility tests were conducted according to the susceptibility testing standard of the Clinical and Laboratory Standards Institute. In the first set, antibacterial susceptibility as measured by the MIC (MIC range) of IMR was assessed for the following 61 imipenem-nonsusceptible strains: 2 Enterobacter cloacae complex (not determined [0.25 μg/mL]), 33 Klebsiella aerogenes (0.5/1 μg/mL [0.5 to 1 μg/mL]), 2 Serratia marcescens (not determined [1 to 2 μg/mL]), and 24 P. aeruginosa (2/128 μg/mL [0.25 to >128 μg/mL]). In the second set, antibacterial susceptibility was assessed for the following 8 imipenem-nonsusceptible strains: 4 Escherichia coli, 1 E. cloacae complex and 3 Klebsiella pneumoniae. The MIC ranges of IMR for these strains were 0.25 to 0.5 μg/mL, 0.5 μg/mL, and 0.5 to 16 μg/mL, respectively. The antibacterial activity of IMR was similar to or lower than that of amikacin and comparable to or greater than those of other reference drugs. In conclusion, IMR has shown antibacterial activity against clinical isolates from Japan and, therefore, is expected to become a new therapeutic option for carbapenem-resistant infections in Japan. Carbapenem-resistant Enterobacterales and carbapenem-resistant Pseudomonas aeruginosa strains pose a global threat. Antibacterial activity of imipenem/relebactam (IMR) against clinical isolates of these bacteria from several global regions has been shown; however, as yet there are no reports on Japanese isolates. In this study, we evaluated the antibacterial activity of IMR against imipenem-nonsusceptible Enterobacterales and Pseudomonas aeruginosa isolates from Japan. The antibacterial activity of IMR against imipenem-nonsusceptible Enterobacterales was generally comparable to that of amikacin (AMK) and comparable to or higher than those of other reference drugs tested. The antibacterial activity of IMR against imipenem-nonsusceptible P. aeruginosa isolates was lower than that of AMK but comparable to or higher than those of other drugs. These results support the use of IMR as a new treatment option for infections due to Enterobacterales and P. aeruginosa strains that are resistant to existing β-lactams and other antibacterial agents.
Topics: Amikacin; Anti-Bacterial Agents; Azabicyclo Compounds; Carbapenems; Imipenem; Japan; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 35416695
DOI: 10.1128/spectrum.02235-21 -
Annals of Laboratory Medicine Jan 2024Limited data are available regarding the activity of SPR719, a derivative of benzimidazole, against diverse nontuberculous mycobacteria (NTM) species. We investigated...
Limited data are available regarding the activity of SPR719, a derivative of benzimidazole, against diverse nontuberculous mycobacteria (NTM) species. We investigated the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of SPR719 against clinical NTM isolates, including clarithromycin- and amikacin-resistant strains. NTM isolates were obtained from patients with NTM-pulmonary disease caused by various NTM species, including complex, (subspecies and ), , and . Regardless of clarithromycin or amikacin resistance, the MIC and MBC values of SPR719 were comparable among these major pathogenic NTM species. In over 70% of the isolates, the MIC values were ≤2 μg/mL with MBC values of ≤4 μg/mL. The MIC and MBC values of were relatively lower than those of the other species with little difference between them, demonstrating the bactericidal properties of SPR719. The activity of SPR719 against major clinical NTM species suggests that SPR719 can serve as a novel treatment option for NTM-pulmonary disease.
Topics: Humans; Clarithromycin; Amikacin; Nontuberculous Mycobacteria; Benzimidazoles; Anti-Bacterial Agents; Mycobacterium Infections, Nontuberculous
PubMed: 37665290
DOI: 10.3343/alm.2024.44.1.92 -
Internal Medicine (Tokyo, Japan) Aug 2022
Topics: Administration, Inhalation; Amikacin; Anti-Bacterial Agents; Humans; Liposomes; Microbial Sensitivity Tests; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Pneumonia
PubMed: 35110485
DOI: 10.2169/internalmedicine.8796-21 -
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 -
BioMed Research International 2022The increasing rates of antimicrobial resistance have demanded the development of new drugs as conventional antibiotics have become significantly less effective....
The increasing rates of antimicrobial resistance have demanded the development of new drugs as conventional antibiotics have become significantly less effective. Evidence has identified a variety of phytocompounds with the potential to be used in the combat of infections caused by multidrug-resistant (MDR) bacteria. Considering the verification that terpenes are promising antibacterial compounds, the present research aimed to evaluate the antibacterial and antibiotic-modulating activity of (+)--pinene and (-)-borneol against MDR bacterial strains. The broth microdilution method was used to determine the minimum inhibitory concentration (MIC) of the compounds and antibiotics and further evaluate the intrinsic and associated antibiotic activity. These analyses revealed that (+)--pinene showed significant antibacterial activity only against (MIC = 512 g.mL), while no significant inhibition of and growth was observed (MIC ≥ 1024 g mL). However, when combined with antibiotics, this compound induced a significant improvement in the activity of conventional antibiotics, as observed for ciprofloxacin, amikacin, and gentamicin against , as well as for amikacin and gentamicin against , and amikacin against . On the other hand, (-)-borneol was found to inhibit the growth of and enhance the antibiotic activity of ciprofloxacin and gentamicin against . The present findings indicate that (+)--pinene and (-)-borneol are phytocompounds with the potential to be used in the combat of antibacterial resistance.
Topics: Amikacin; Anti-Bacterial Agents; Bicyclic Monoterpenes; Camphanes; Ciprofloxacin; Escherichia coli; Gentamicins; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Staphylococcus aureus
PubMed: 35663042
DOI: 10.1155/2022/8217380 -
F1000Research 2022Carbapenems are the treatment of choice for multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections, but the emergence of...
Carbapenems are the treatment of choice for multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections, but the emergence of carbapenem-resistant (CRAB) has rendered it ineffective in the vast majority of cases. Combination therapy has grown in popularity over the last decade; this study aims to analyze growth kinetics after exposure to meropenem and ampicillin-sulbactam compared with meropenem and amikacin antibiotic combinations in clinically relevant concentrations. This experimental laboratory study was conducted on the ATCC 19606 isolate and three clinical isolates that were intermediate or resistant to tested antibiotics. Meropenem and ampicillin-sulbactam, as well as meropenem and amikacin, were tested at four different concentrations against isolates. Turbidity measurements were taken at predetermined time points of 0, 1, 2, 4, 6, 8, and 24 hours following exposure; bacterial concentration was enumerated using the agar plate method, with the results plotted in a time-kill curve. A bactericidal effect was achieved in isolates that were intermediate to ampicillin-sulbactam and resistant to meropenem after the administration of meropenem and ampicillin-sulbactam combination with a concentration of 4 µg/ml and 16/8 µg/ml, respectively. The combination of meropenem and ampicillin-sulbactam demonstrated bacteriostatic activity against isolates that were resistant to both antibiotics. Isolates treated with resistant antibiotics showed an increased growth rate compared to the growth control. The combination of meropenem and ampicillin-sulbactam could be a promising combination therapy in treating CRAB infections. The mechanism and degree of antibiotic resistance in the isolates affect the efficacy of antibiotic combinations; further research is needed to corroborate the findings of this study.
Topics: Humans; Meropenem; Acinetobacter baumannii; Amikacin; Kinetics; Anti-Bacterial Agents; Carbapenems; Acinetobacter Infections
PubMed: 36531260
DOI: 10.12688/f1000research.122221.2 -
Veterinary Medicine and Science Mar 2023One of the most common causes of pneumonia is Pseudomonas aeruginosa (P. aeruginosa). As with other microbial pathogens, this bacterium tends to develop resistance to...
BACKGROUND
One of the most common causes of pneumonia is Pseudomonas aeruginosa (P. aeruginosa). As with other microbial pathogens, this bacterium tends to develop resistance to various antibiotics. Amikacin and erythromycin, which are from the aminoglycoside and macrolide antibiotic families, are used to treat respiratory infections caused by P. aeruginosa.
OBJECTIVES
This study explored whether amikacin, erythromycin or a combination of both works better against P. aeruginosa acute lung infection.
METHODS
For this study, 32 rats were used. The trachea of rats was exposed aseptically and their lung was infected with P. aeruginosa through trachea. Then, according to the group, they received amikacin, erythromycin or a combination of both for 1 week. Finally, they were euthanised on the 3rd and 7th days post-infection. The macroscopic and microscopic evaluations of the lungs, kidney and liver were performed. The right lung was collected for in vivo bacteriological analysis.
RESULTS
The amikacin group (A group) had a statistically significantly lower macroscopic and microscopic scores than the other groups (p < 0.05). In vivo bacteriological test revealed that the A group had significantly lower lung bacterial load (p < 0.05).
CONCLUSIONS
In summary, it was concluded that amikacin could help alleviate the respiratory infection caused by P. aeruginosa solely, and it was more effective than erythromycin.
Topics: Animals; Rats; Amikacin; Anti-Bacterial Agents; Erythromycin; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Disease Models, Animal
PubMed: 36318447
DOI: 10.1002/vms3.991 -
Antimicrobial Agents and Chemotherapy Mar 2018Amikacin, kanamycin, and capreomycin are among the most important second-line drugs for multidrug-resistant tuberculosis. Although amikacin and kanamycin are...
Amikacin, kanamycin, and capreomycin are among the most important second-line drugs for multidrug-resistant tuberculosis. Although amikacin and kanamycin are administered at the same dose and show the same pharmacokinetics, they have different WHO breakpoints, suggesting that the two drugs have different MICs. The aim of this study was to investigate possible differences in MICs between the aminoglycosides and capreomycin. Using the direct concentration method, a range of concentrations of amikacin, kanamycin, and capreomycin (0.25, 0.50, 1.0, 2.0, 4.0, 8.0, 16.0, 32.0, and 64.0 mg/liter) were tested against 57 clinical strains. The 7H10 agar plates were examined for mycobacterial growth after 14 days. At 2 mg/liter, 48 strains (84%) were inhibited by amikacin and only 5 strains (9%) were inhibited by kanamycin ( < 0.05, Wilcoxon signed-rank test). The median MICs of amikacin, kanamycin, and capreomycin were 2, 4, and 8 mg/liter, respectively. No difference in amikacin, kanamycin, and capreomycin MIC distributions was observed between multidrug-resistant strains and fully susceptible strains. The results indicate that amikacin is more active than kanamycin and capreomycin against with the absolute concentration method. Determination of the impact of this difference on clinical outcomes in daily practice requires a prospective study, including pharmacokinetic and pharmacodynamic evaluations.
Topics: Amikacin; Capreomycin; Glycopeptides; Kanamycin; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 29311078
DOI: 10.1128/AAC.01724-17 -
Antimicrobial Agents and Chemotherapy Jul 2023Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of...
Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of the bacteria, combination therapy of three or more antibiotics is recommended. A major challenge in treating M. abscessus infections is the absence of a universal combination therapy with satisfying clinical success rates, leaving clinicians to treat infections using antibiotics lacking efficacy data. We systematically measured drug combinations in M. abscessus to establish a resource of drug interaction data and identify patterns of synergy to help design optimized combination therapies. We measured 191 pairwise drug combination effects among 22 antibacterials and identified 71 synergistic pairs, 54 antagonistic pairs, and 66 potentiator-antibiotic pairs. We found that commonly used drug combinations in the clinic, such as azithromycin and amikacin, are antagonistic in the lab reference strain ATCC 19977, whereas novel combinations, such as azithromycin and rifampicin, are synergistic. Another challenge in developing universally effective multidrug therapies for M. abscessus is the significant variation in drug response between isolates. We measured drug interactions in a focused set of 36 drug pairs across a small panel of clinical isolates with rough and smooth morphotypes. We observed strain-dependent drug interactions that cannot be predicted from single-drug susceptibility profiles or known drug mechanisms of action. Our study demonstrates the immense potential to identify synergistic drug combinations in the vast drug combination space and emphasizes the importance of strain-specific combination measurements for designing improved therapeutic interventions.
Topics: Humans; Mycobacterium abscessus; Azithromycin; Anti-Bacterial Agents; Amikacin; Mycobacterium Infections, Nontuberculous; Drug Interactions; Microbial Sensitivity Tests
PubMed: 37278639
DOI: 10.1128/aac.00090-23