Amikacin levels in bronchial secretions of 10 pneumonia patients with respiratory support treated once daily versus twice daily

Santré, Ch.; Georges, Hugues; Jacquier, J M; Leroy, Olivier; Beuscart, C.; Buguin, D; Beaucaire, G.

doi:10.1128/aac.39.1.264

Cited by 38 publications

(20 citation statements)

References 12 publications

(14 reference statements)

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“…Although aminoglycosides are distributed almost freely in the extracellular space of most tissues because of their minimal protein binding and high water solubility, they cross biological membranes poorly, so drug concentrations in bronchial secretions are low, thus restricting their efficacy in the treatment of respiratory tract infections (158)(159)(160)(161)(162). Low concentrations of aminoglycosides in the respiratory tract upon intravenous dosing are due to their polycationic charge and their lipid insolubility (163).…”

Section: Serum and Sputum Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Dalhoff¹

2014

Clin Microbiol Rev

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SUMMARY Bacteria adapt to growth in lungs of patients with cystic fibrosis (CF) by selection of heterogeneously resistant variants that are not detected by conventional susceptibility testing but are selected for rapidly during antibacterial treatment. Therefore, total bacterial counts and antibiotic susceptibilities are misleading indicators of infection and are not helpful as guides for therapy decisions or efficacy endpoints. High drug concentrations delivered by aerosol may maximize efficacy, as decreased drug susceptibilities of the pathogens are compensated for by high target site concentrations. However, reductions of the bacterial load in sputum and improvements in lung function were within the same ranges following aerosolized and conventional therapies. Furthermore, the use of conventional pharmacokinetic/pharmacodynamic (PK/PD) surrogates correlating pharmacokinetics in serum with clinical cure and presumed or proven eradication of the pathogen as a basis for PK/PD investigations in CF patients is irrelevant, as minimization of systemic exposure is one of the main objectives of aerosolized therapy; in addition, bacterial pathogens cannot be eradicated, and chronic infection cannot be cured. Consequently, conventional PK/PD surrogates are not applicable to CF patients. It is nonetheless obvious that systemic exposure of patients, with all its sequelae, is minimized and that the burden of oral treatment for CF patients suffering from chronic infections is reduced.

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Section: Serum and Sputum Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Dalhoff¹

2014

Clin Microbiol Rev

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“…We achieved an AUC 0 -24 /MIC of 5.3 mg · h/liter for clarithromycin, a percentage of time above the MIC of 100% for cefoxitin, and an fC max /MIC of 4.0 of amikacin, so that each drug was at optimal free-drug exposure (3). These exposures are actually better than those achieved in most patients with standard dosing, based on prior work (3,6,7,9).We sampled each system's peripheral compartment on days 0, 1, 2, 3, 5, 7, 10, 14, 21, and 28 of treatment, washed the cultures in saline to avoid antibiotic carryover, serially diluted the cultures, and cultured them on antibiotic-free Middlebrook 7H10 agar. The size of the resistant subpopulation was quantified by culturing on Middlebrook agar plates containing 3 times the MIC of each antibiotic.…”

mentioning

confidence: 99%

Failure of the Amikacin, Cefoxitin, and Clarithromycin Combination Regimen for Treating Pulmonary Mycobacterium abscessus Infection

Ferro

Srivastava

Deshpande

et al. 2016

Antimicrob Agents Chemother

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In a hollow-fiber model, we mimicked the drug exposures achieved in the lungs of humans treated with standard amikacin, clarithromycin, and cefoxitin combination therapy for Mycobacterium abscessus infection. At optimal dosing, a kill rate of ؊0.09 (95% confidence interval, ؊0.04 to 0.03) log 10 CFU per ml/day was achieved over the first 14 days, after which there was regrowth due to acquired drug resistance. Thus, the standard regimen quickly failed. A new regimen is needed. Clinicians treat Mycobacterium abscessus pulmonary disease with a combination of amikacin, clarithromycin, and cefoxitin for 1 to 2 months, followed by an oral maintenance regimen, usually with a fluoroquinolone, based on the recommendations of experts (1). However, the use of this approach "cures" only 50% even with adjunctive surgery, most of whom relapse or die (2). We have developed a hollow-fiber model of M. abscessus (HFS-M. abscessus) and evaluated the effect of monotherapy of amikacin and moxifloxacin in the system. Each drug failed dramatically, and acquired drug resistance (ADR) developed (3, 4). Since these drugs are given as combination therapy in patients, they could still work in combination. Here, we evaluated the performance of the standard combination regimen of amikacin, cefoxitin, and clarithromycin in the HFS-M. abscessus to determine potential synergy, and even more importantly, whether the combination therapy could prevent ADR.Antibiotics were purchased from the Baylor University Medical Center Pharmacy (Dallas, TX) and from Sigma-Aldrich (St. Louis, MO). Antibiotics were dissolved in water-methanol (clarithromycin), sterile filtered, and diluted to the desired concentrations in Middlebrook 7H9 broth (here broth; Remel, Lenexa, KS). Stock solutions of M. abscessus ATCC 19977 (ATCC, Manassas, VA) were grown to logarithmic-growth phase in the broth. MICs were measured using broth microdilution (5). The amikacin, cefoxitin, and clarithromycin MICs were 32, 16, and 8 mg/liter, respectively.The peripheral compartments of six HFS-M. abscessus systems were inoculated with 20 ml of 6.0 log 10 CFU/ml M. abscessus, as previously described (3). Three systems were immediately treated with a combination of amikacin, cefoxitin, and clarithromycin, while three replicate systems were nontreated controls. Amikacin, cefoxitin, and clarithromycin were administered via syringe pumps for 28 days, as in patients. We mimicked free-drug area under the concentration-time curve from 0 to 24 h (fAUC 0 -24 ), peak concentration (fC max ), and time to maximum concentration achieved in the lungs of humans treated with amikacin and clarithromycin administered once daily, at 1,000 mg, and cefoxitin administered at 2 g four times a day (6, 7). Different half-lives in each HFS-M. abscessus system were achieved, as described by us in the past (8). Antibiotic concentrations achieved in all the systems were validated by sampling from the central compartment of each system at seven time points over 24 h postdose, after which concentrations were assayed in ...

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“…First, Monte Carlo simulations were performed to identify the C max , AUC 0 -24 , and concentration-time profiles achieved by doses of 750, 1,000, 1,500, 2,000, 3,000, and 4,000 mg in 10,000 patients. Since at steady state with once-a-day dosing in patients with pneumonia, peak concentrations in bronchial secretion are only 40.5% of those in serum, and the AUC 0 -24 is only 81% of those in serum, these penetration ratios into the lung were taken into account (15). Next, we introduced the effect of MIC variability, based on the MICs identified in 44 patients seen by one of us (J.V.I.)…”

mentioning

confidence: 99%

“…Dose-scheduling studies were simultaneously performed; we tested human-like doses of 500, 2,000, and 4,000 mg, chosen based on the pilot concentration-effect study in test tubes, to be administered thrice daily in order to match some of the C max /MIC and percent time the concentration remains above the MIC (%T MIC ) in the once-a-day regimens. The dilution rates were set to achieve an amikacin half-life of 3 h, as encountered in serum and bronchial secretions (14,15). The amikacin concentrations achieved in all the HFS were validated by sampling each central compartment during the last 2 days at 0, 0.5, 2.7, 5.…”

mentioning

confidence: 99%

Amikacin Pharmacokinetics/Pharmacodynamics in a Novel Hollow-Fiber Mycobacterium abscessus Disease Model

Ferro

Srivastava

Deshpande

et al. 2016

Antimicrob Agents Chemother

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fThe treatment of pulmonary Mycobacterium abscessus disease is associated with very high failure rates and easily acquired drug resistance. Amikacin is the key drug in treatment regimens, but the optimal doses are unknown. No good preclinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments to determine these optimal doses. We developed a hollow-fiber system model of M. abscessus disease and studied amikacin exposure effects and dose scheduling. We mimicked amikacin human pulmonary pharmacokinetics. Both amikacin microbial kill and acquired drug resistance were linked to the peak concentration-to-MIC ratios; the peak/MIC ratio associated with 80% of maximal kill (EC 80 ) was 3.20. However, on the day of the most extensive microbial kill, the bacillary burden did not fall below the starting inoculum. We performed Monte Carlo simulations of 10,000 patients with pulmonary M. abscessus infection and examined the probability that patients treated with one of 6 doses from 750 mg to 4,000 mg would achieve or exceed the EC 80 . We also examined these doses for the ability to achieve a cumulative area under the concentration-time curve of 82,232 mg · h/liter ؋ days, which is associated with ototoxicity. The standard amikacin doses of 750 to 1,500 mg a day achieved the EC 80 in <21% of the patients, while a dose of 4 g/day achieved this in 70% of the patients but at the cost of high rates of ototoxicity within a month or two. The susceptibility breakpoint was an MIC of 8 to 16 mg/liter. Thus, amikacin, as currently dosed, has limited efficacy against M. abscessus. It is urgent that different antibiotics be tested using our preclinical model and new regimens developed. Mycobacterium abscessus is a rapidly growing mycobacterium (RGM) responsible for about 80% of all pulmonary infections caused by RGM (1). It is one of the most drug-resistant microorganisms encountered in the clinic, far worse than extensively and totally drug-resistant Mycobacterium tuberculosis; this is a reason why it is considered the "new antibiotic nightmare" (2). The current treatment for M. abscessus diseases varies according to the infecting subspecies (3); in general, it involves a backbone of amikacin in combination with clarithromycin and either cefoxitin or imipenem early during therapy, followed by subsequent use of oral antibiotics, which is analogous to the initial and continuation phases of tuberculosis treatment (1). Unfortunately, at least half of the patients either fail this therapy, relapse, or die; there is no reliable antibiotic regimen that cures M. abscessus lung disease (1, 4). Several other regimens have been tried and found wanting. In such regimens and the standard regimen, the doses were chosen based on what has worked well in mundane Gramnegative bacilli. No formal antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) analyses have been performed with M. abscessus. Our time-kill assays in the past demonstrated that amikacin was the most active antibiotic compared to cefoxitin and clarithromycin (5)....

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Amikacin levels in bronchial secretions of 10 pneumonia patients with respiratory support treated once daily versus twice daily

Cited by 38 publications

References 12 publications

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Failure of the Amikacin, Cefoxitin, and Clarithromycin Combination Regimen for Treating Pulmonary Mycobacterium abscessus Infection

Amikacin Pharmacokinetics/Pharmacodynamics in a Novel Hollow-Fiber Mycobacterium abscessus Disease Model

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