Bronchial Secretion Levels of Amikacin

In this study, concentrations of amikacin in blood and bronchial secretions of 10 patients with mechanical ventilation for acute respiratory failure due to pneumonia were measured. One-half of the patients received amikacin twice daily, and the others received once-daily administration. Concentrations in bronchial secretions of the patients treated twice daily ranged from 3 to 4 mg/liter, i.e., they were similar to those in previously published reports. Peak concentrations in bronchial secretions occurred between 3 and 4 h after the onset of infusion, and they reached 4.8 ؎ 2.6 mg/liter on day 1 and 4.0 ؎ 2.7 mg/liter on day 3. For the patients treated with amikacin once daily, concentrations in bronchial secretions were more than twofold higher, above 8 mg/liter for 12 h. Peak concentrations in bronchial secretions occurred between 3 and 4 h after the onset of infusion and reached 13.6 ؎ 9.3 mg/liter on day 1 and 10.4 ؎ 3.5 mg/liter on day 3. These concentrations are higher than the MICs for less sensitive bacterial strains, such as Acinetobacter spp. and Pseudomonas aeruginosa.

“…These results for the bid treatment group are consistent with previous observations with amikacin (6,8). The reported MICs of amikacin for Acinetobacter spp.…”

supporting

confidence: 83%

supporting

confidence: 83%

mentioning

confidence: 99%

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

Santré

Georges

Jacquier

et al. 1995

“…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

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)....

“…Antibiotic concentrations in blood are compared with the MIC for the infecting organism in an attempt to determine whether the antibiotic will be available in sufficient concentration to be effective. However, it has been demonstrated that even though adequate concentrations of aminoglycoside antibiotics are achievable in the blood, levels in bronchial secretions may be substantially lower (1,4). Such low antibiotic concentrations in bronchial secretions may contribute to the continuing high mortality rate for gram-negative-bacillary pneumonias.…”

mentioning

confidence: 99%

Penetration of cefotaxime into respiratory secretions

Fick¹,

Alexander²,

Prince³

et al. 1987

The objective of this study was to quantitate cefotaxime and its active metabolite, desacetyl cefotaxime, in the distal airways and to compare these levels to concentrations in plasma. Respiratory secretions were obtained from the subsegmental level in 17 adult patients undergoing fiber-optic bronchoscopy within 2 h after receiving four doses of cefotaxime (2 g intravenously every 6 h). In 11 patients, cefotaxime levels measured by high-pressure liquid chromatography in bronchial secretions were below detectable limits (<0.5 mg/liter); however, levels of desacetyl cefotaxime exceeded 1.5 mg/liter in 9 of these 11 patients (range, 1.6 to 10 mg/liter).Concentrations of desacetyl cefotaxime in lung secretions (6.9 + 0.85 [standard error] mg/liter) was 77% of mean levels of desacetyl cefotaxime in plasma (8.9 + 1.26 mg/liter). In summary, concentrations of desacetyl cefotaxime in bronchial secretions are markedly higher than those of cefotaxime.Gram-negative-bacillary pneumonias are commonly treated with aminoglycoside antibiotics because other equally effective and less toxic agents have not been available. These lung infections respond to therapy slowly, are subject to relapse, and still have a mortality rate of 50%, despite the use of seemingly appropriate antimicrobial therapy (8,9). It is a common practice to determine antibiotic concentrations in the blood and to extrapolate this information to other tissues and body fluids in which the antibiotic may be less accessible. Antibiotic concentrations in blood are compared with the MIC for the infecting organism in an attempt to determine whether the antibiotic will be available in sufficient concentration to be effective. However, it has been demonstrated that even though adequate concentrations of aminoglycoside antibiotics are achievable in the blood, levels in bronchial secretions may be substantially lower (1, 4). Such low antibiotic concentrations in bronchial secretions may contribute to the continuing high mortality rate for gram-negative-bacillary pneumonias. Therefore, the goal of this study was to quantitate the potent broadspectrum cephalosporin, cefotaxime (CFX), and its active metabolite, desacetyl cefotaxime (DCFX), in the secretions of the distal airway of human subjects and then to relate these levels in lung secretions to concentrations in serum.The study protocol was designed to compare concentrations of CFX The antibiotic (2 g) was administered by intravenous infusion over a 5-to 10-min period every 6 h.Whole blood specimens (10 ml) were obtained at the same time as bronchial secretions. Blood samples were immediately centrifuged, and plasma was removed and preserved at -70°C until analysis was performed. Bronchoscopy permitted collection of undiluted respiratory secretions from the 4th-to 8th-generation airways and was performed as previously described (5,12). The respiratory secretions collected by this means (1-to 4-ml samples) were stored at -70°C until they were assayed by high-pressure liquid chromatography for CFX and DCFX. Plasma sampl...