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Antimicrobial Agents and Chemotherapy Nov 2020Combination therapy may enhance imipenem/cilastatin/relebactam's (I/R) activity against and suppress resistance development. Human-simulated unbound plasma...
Combination therapy may enhance imipenem/cilastatin/relebactam's (I/R) activity against and suppress resistance development. Human-simulated unbound plasma concentrations of I/R at 1.25 g every 6 h (h), colistin at 360 mg daily, and amikacin at 25 mg/kg daily were reproduced alone and in combination against six imipenem-nonsusceptible isolates in an pharmacodynamic model over 24 h. For I/R alone, the mean reductions in CFU ± the standard errors by 24 h were -2.52 ± 0.49, -1.49 ± 0.49, -1.15 ± 0.67, and -0.61 ± 0.10 log CFU/ml against isolates with MICs of 1/4, 2/4, 4/4, and 8/4 μg/ml, respectively. Amikacin alone also resulted in 24 h CFU reductions consistent with its MIC, while colistin CFU reductions did not differ. Resistant subpopulations were observed after 24 h in 1, 4, and 3 I/R-, colistin-, and amikacin-exposed isolates, respectively. The combination of I/R and colistin resulted in synergistic ( = 1) or additive ( = 2) interactions against three isolates with 24-h CFU reductions ranging from -2.62 to -4.67 log CFU/ml. The combination of I/R and amikacin exhibited indifferent interactions against all isolates, with combined drugs achieving -0.51- to -3.33-log CFU/ml reductions. No resistant subpopulations were observed during I/R and colistin combination studies, and when added to amikacin, I/R prevented the emergence of amikacin resistance. Against these six multidrug-resistant , I/R alone achieved significant CFU reductions against I/R-susceptible isolates. Combinations of I/R plus colistin resulted in additivity or synergy against some , whereas the addition of amikacin did not provide further antibacterial efficacy against these isolates.
Topics: Amikacin; Anti-Bacterial Agents; Azabicyclo Compounds; Cilastatin; Colistin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Imipenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 33139283
DOI: 10.1128/AAC.01764-20 -
Current Opinion in Pulmonary Medicine May 2019To describe recent developments in trials exploring inhaled antibiotics for treating severe pneumonia. (Review)
Review
PURPOSE OF REVIEW
To describe recent developments in trials exploring inhaled antibiotics for treating severe pneumonia.
RECENT FINDINGS
Three recent randomized studies investigated the potential role for aerosolized antibiotics for gram-negative pneumonia in ventilated patients. One single center, nonblinded investigation suggested a benefit with inhaled amikacin for resistant gram-negative infections. However, two multicenter, blinded trials found no benefit to adjunctive nebulized amikacin for severe gram-negative pneumonia.
SUMMARY
Well done clinical trials do not support the routine use of inhaled amikacin for pneumonia in ventilated patients. There may be a potential role for aerosolized antibiotics when other options are limited.
Topics: Administration, Inhalation; Amikacin; Anti-Bacterial Agents; Humans; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated
PubMed: 30562188
DOI: 10.1097/MCP.0000000000000557 -
BMJ Case Reports Apr 2024Catheter-related bloodstream infection (CRBSI) is one of the common healthcare-acquired infections imposing a high burden of morbidity and mortality on the patients....
Catheter-related bloodstream infection (CRBSI) is one of the common healthcare-acquired infections imposing a high burden of morbidity and mortality on the patients. Non-tuberculous mycobacterium is a rare aetiology for CRBSI and poses challenges in laboratory diagnosis and clinical management. This is a case of a woman in her early 60s with underlying end-stage renal failure, diabetes mellitus and hypertension presented with a 2-week history of high-grade fever postregular haemodialysis, vomiting, lethargy and altered mental status.Blood cultures from a permanent catheter and peripheral taken concurrently yielded , identified by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry, which established the diagnosis of CRBSI atypically presented with concurrent acute intracranial bleeding and cerebrovascular infarction at initial presentation. She was started on a combination of oral azithromycin, oral amikacin and intravenous imipenem, and the permanent catheter was removed. Despite the treatments instituted, she developed septicaemia, acute myocardial infarction and macrophage activation-like syndrome, causing the patient's death.
Topics: Humans; Female; Catheter-Related Infections; Mycobacterium Infections, Nontuberculous; Middle Aged; Anti-Bacterial Agents; Fatal Outcome; Bacteremia; Renal Dialysis; Kidney Failure, Chronic; Amikacin
PubMed: 38688568
DOI: 10.1136/bcr-2024-259761 -
Medecine Et Maladies Infectieuses Nov 2020We aimed to evaluate the probability to achieve PK-PD targets in patients with sepsis hospitalized in the intensive care unit (ICU) after a single dose of 30mg/kg of...
OBJECTIVES
We aimed to evaluate the probability to achieve PK-PD targets in patients with sepsis hospitalized in the intensive care unit (ICU) after a single dose of 30mg/kg of amikacin or 8mg/kg of gentamicin.
PATIENTS AND METHODS
This single-center prospective study included 138 ICU patients with severe sepsis or septic shock with an indication for intravenous amikacin (N=89) or gentamicin (N=49). Maximum concentration (C) was measured 30 minutes after infusion completion. PK/PD objectives were respectively C≥60mg/L and ≥30mg/L for amikacin and gentamicin for empirical therapy, and a C/MIC ratio≥8, as per French guidelines.
RESULTS
The median Simplified Acute Physiology Score II was 43 and ICU case fatality rate was 34.8%. A causative bacterial agent was identified in 94 patients (68.1%). Three pathogens had acquired aminoglycoside resistance and 15 were naturally resistant. The targeted C for the first dose was achieved in 53 patients (59.6%) receiving amikacin, and one (2.2%) patient receiving gentamicin. C/MIC ratio≥8 was obtained in all patients infected with susceptible pathogens (N=72). Factors associated with C≥60mg/L of amikacin in multivariate analysis were dose per kg of adapted body weight (OR=1.39, P<0.001) and renal clearance estimated with CKD-EPI formula (OR=0.98, P=0.003).
CONCLUSIONS
Despite high doses, amikacin and gentamicin first C remain dramatically low in ICU patients. However, an adequate C/MIC ratio was reached in all patients.
Topics: Amikacin; Anti-Bacterial Agents; Gentamicins; Humans; Intensive Care Units; Prospective Studies
PubMed: 31883736
DOI: 10.1016/j.medmal.2019.12.003 -
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 -
Pulmonary Pharmacology & Therapeutics Aug 2019Nebulization during mechanical ventilation is impeded by large extra-pulmonary drug deposition and long administration durations which currently limit implementation of...
BACKGROUND
Nebulization during mechanical ventilation is impeded by large extra-pulmonary drug deposition and long administration durations which currently limit implementation of inhaled antibiotic therapy. Direct intra-tracheal delivery using a sprayer represents an appealing alternative investigated in small animal models, but large animal data are lacking.
METHODS
Amikacin was administered through intravenous infusion (20 mg/kg), nebulization (60 mg/kg) and direct intra-tracheal spray (30 mg/kg) to 10 intubated piglets, in a randomized cross-over design. Amikacin concentrations were measured in the serum and pulmonary parenchyma. Anatomic deposition was investigated using immuno-histochemistry.
RESULTS
Spray delivery resulted in higher amikacin outputs than nebulization and infusion. Pulmonary inhaled delivery techniques yielded much higher lung concentrations and much lower serum concentrations than intravenous infusion. However, unlike nebulization and infusion, intra-tracheal spray delivery was associated with more than 100- and 1000-fold variability in lung concentrations between and within animals. Amikacin specific immuno-histochemistry showed consistent bronchial and alveolar drug deposition with all modalities.
CONCLUSION
Nebulization remains the most reliable and simple technique to deliver inhaled amikacin uniformly to the lung during mechanical ventilation. Further development of tracheal sprays is required to take advantage of potential benefits related to high drug output and low extra-pulmonary deposition in large animals.
Topics: Aerosols; Amikacin; Animals; Anti-Bacterial Agents; Drug Delivery Systems; Infusions, Intravenous; Inhalation; Intubation; Lung; Models, Anatomic; Models, Animal; Nebulizers and Vaporizers; Swine; Trachea
PubMed: 31102741
DOI: 10.1016/j.pupt.2019.101807 -
Clinics in Chest Medicine Dec 2023Treatment of M avium pulmonary disease requires a three-drug, macrolide-based regimen that is administered for 12 months beyond culture conversion. The regimen can be... (Review)
Review
Treatment of M avium pulmonary disease requires a three-drug, macrolide-based regimen that is administered for 12 months beyond culture conversion. The regimen can be administered 3 days a week in non-cavitary, nodular bronchiectatic disease but should be given daily when cavitary disease is present. For treatment refractory disease, amikacin liposome inhalation suspension is added to the regimen. Parenteral amikacin or streptomycin should be administered in the setting of extensive radiographic involvement or macrolide resistance. Recurrence of disease is common and often due to reinfection. Novel and repurposed agents are being evaluated in clinical trials.
Topics: Humans; Mycobacterium avium Complex; Anti-Bacterial Agents; Amikacin; Mycobacterium avium-intracellulare Infection; Macrolides; Treatment Outcome; Drug Resistance, Bacterial; Lung Diseases
PubMed: 37890915
DOI: 10.1016/j.ccm.2023.06.009 -
Antimicrobial Agents and Chemotherapy Mar 2024Amikacin is an FDA-approved aminoglycoside antibiotic that is commonly used. However, validated dosage regimens that achieve clinically relevant exposure profiles in...
Population pharmacokinetics and humanized dosage regimens matching the peak, area, trough, and range of amikacin plasma concentrations in immune-competent murine bloodstream and lung infection models.
Amikacin is an FDA-approved aminoglycoside antibiotic that is commonly used. However, validated dosage regimens that achieve clinically relevant exposure profiles in mice are lacking. We aimed to design and validate humanized dosage regimens for amikacin in immune-competent murine bloodstream and lung infection models of . Plasma and lung epithelial lining fluid (ELF) concentrations after single subcutaneous doses of 1.37, 13.7, and 137 mg/kg of body weight were simultaneously modeled via population pharmacokinetics. Then, humanized amikacin dosage regimens in mice were designed and prospectively validated to match the peak, area, trough, and range of plasma concentration profiles in critically ill patients (clinical dose: 25-30 mg/kg of body weight). The pharmacokinetics of amikacin were linear, with a clearance of 9.93 mL/h in both infection models after a single dose. However, the volume of distribution differed between models, resulting in an elimination half-life of 48 min for the bloodstream and 36 min for the lung model. The drug exposure in ELF was 72.7% compared to that in plasma. After multiple q6h dosing, clearance decreased by ~80% from the first (7.35 mL/h) to the last two dosing intervals (~1.50 mL/h) in the bloodstream model. Likewise, clearance decreased by 41% from 7.44 to 4.39 mL/h in the lung model. The humanized dosage regimens were 117 mg/kg of body weight/day in mice [administered in four fractions 6 h apart (q6h): 61.9%, 18.6%, 11.3%, and 8.21% of total dose] for the bloodstream and 96.7 mg/kg of body weight/day (given q6h as 65.1%, 16.9%, 10.5%, and 7.41%) for the lung model. These validated humanized dosage regimens and population pharmacokinetic models support translational studies with clinically relevant amikacin exposure profiles.
Topics: Humans; Animals; Mice; Amikacin; Anti-Bacterial Agents; Lung; Pneumonia; Body Weight
PubMed: 38289076
DOI: 10.1128/aac.01394-23 -
Therapeutic Drug Monitoring Aug 2019The influence of cancer cachexia on the pharmacokinetics of and kidney injury caused by amikacin remains unclear. This study investigated whether the pharmacokinetics of...
BACKGROUND
The influence of cancer cachexia on the pharmacokinetics of and kidney injury caused by amikacin remains unclear. This study investigated whether the pharmacokinetics of amikacin and the risk of kidney injury are altered with the progression of cancer cachexia.
METHODS
A retrospective analysis was conducted using therapeutic drug monitoring data obtained from 52 cancer patients who received amikacin intravenously for infection(s). The patients were classified into 2 groups based on the status of cachexia using a consensus definition: noncachexia group (n = 31) and cachexia group (n = 21). Differences in amikacin pharmacokinetics and occurrence of kidney injury were compared between the 2 groups. Amikacin pharmacokinetics was calculated based on a 1-compartment model using peak and trough concentrations measured clinically for therapeutic drug monitoring. In addition, intrapatient analysis was conducted based on patients who received amikacin treatments more than once during the study period to examine the alteration in amikacin pharmacokinetics with the progression of cancer cachexia.
RESULTS
Systemic clearance of amikacin [median (range)] was significantly (P < 0.05) lower in the cachexia group [37.3 (11.2-87.3) (mL/min)] than in the noncachexia group [52.0 (19.1-133.4) (mL/min)]. In contrast, volume of distribution was significantly (P < 0.05) increased in the cachexia group [0.47 (0.20-1.45) L/kg] compared with the noncachexia group [0.32 (0.21-1.00) L/kg]. There was no difference in the occurrence of kidney injuries between the 2 groups. In an intrapatient analysis of the longitudinal alteration of amikacin pharmacokinetics, an approximately 50% reduction in clearance and 30% increase in volume of distribution were observed as cancer cachexia progressed.
CONCLUSIONS
The present study suggests that progression of cancer cachexia may reduce amikacin clearance and increase the volume of distribution, but cancer cachexia does not increase amikacin-induced kidney injury.
Topics: Adult; Aged; Aged, 80 and over; Amikacin; Anti-Bacterial Agents; Creatinine; Disease Progression; Female; Hematologic Neoplasms; Humans; Kidney Diseases; Male; Middle Aged; Retrospective Studies; Young Adult
PubMed: 30817701
DOI: 10.1097/FTD.0000000000000621 -
Computer Methods and Programs in... Dec 2022Model-based analysis of longitudinal optical density measurements from a bacterial suspension exposed to antibiotics has been proposed as a potentially efficient and...
BACKGROUND
Model-based analysis of longitudinal optical density measurements from a bacterial suspension exposed to antibiotics has been proposed as a potentially efficient and effective method for extracting useful information to improve the individualized design of treatments for bacterial infections. To that end, the authors developed in previous work a mathematical modeling framework that can use such measurements for design of effective dosing regimens.
OBJECTIVES
Here we further explore ways to extract information from longitudinal optical density measurements to predict bactericidal efficacy of clinically relevant antibiotic exposures.
METHODS
Longitudinal optical density measurements were collected in an automated instrument where Acinetobacter baumannii, ATCC BAA747, was exposed to ceftazidime concentrations of 1, 4, 16, 64, and 256 mg/L and to ceftazidime/amikacin concentrations of 1/0.5, 4/2, 16/8, 64/32, and 256/128 (mg/L)/(mg/L) over 20 h. Calibrated conversion of measurements produced total (both live and dead) bacterial cell concentration data (CFU/mL equivalent) over time. Model-based data analysis predicted the bactericidal efficacy of ceftazidime and of ceftazidime/amikacin (at ratio 2:1) for periodic injection every 8 h and subsequent exponential decline with half-life of 2.5 h. Predictions were experimentally tested in an in vitro hollow-fiber infection model, using peak concentrations of 60 and 150 mg/L for injected ceftazidime and of 40/20 (mg/L)/(mg/L) for injected ceftazidime/amikacin.
RESULTS
Model-based analysis predicted low (<62%) confidence in clinically relevant suppression of the bacterial population by periodic injections of ceftazidime alone, even at high peak concentrations. Conversely, analysis predicted high (>95%) confidence in bacterial suppression by periodic injections of ceftazidime/amikacin combinations at a wide range of peak concentrations ratioed at 2:1. Both predictions were experimentally confirmed in an in vitro hollow fiber infection model, where ceftazidime was periodically injected at peak concentrations 60 and 150 mg/L (with predicted suppression confidence 38% and 59%, respectively) and a combination of ceftazidime/amikacin was periodically injected at peak concentrations 40/20 (mg/L)/(mg/L) (with predicted suppression confidence 98%).
CONCLUSIONS
The paper highlights the potential of clinicians using the proposed mathematical framework to determine the utility of different antibiotics to suppress a patient-specific isolate. Additional studies will be needed to consolidate and expand the utility of the proposed method.
Topics: Humans; Ceftazidime; Amikacin; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 36335752
DOI: 10.1016/j.cmpb.2022.107212