Sputum antibiotic concentrations: Implications for treatment of cystic fibrosis lung infection

Moriarty, T. Fintan; McElnay, James; Elborn, J. Stuart; Tunney, Michael

doi:10.1002/ppul.20671

Cited by 55 publications

(38 citation statements)

References 46 publications

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“…In regard to the disposition of CAZ in sputum, no discernible pattern was observed to afford incorporation of this compartment into our model; however, point estimates of exposure reported here are comparable to those found in previously published reports (see Fig. S4 in the supplemental material) (19,21,22). Taken together, our results suggest that the pharmacokinetics of CAZ in patients with CF are similar to those in healthy subjects.…”

Section: Discussionsupporting

confidence: 79%

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis

Bensman

Wang

Jayne

et al. 2017

Antimicrob Agents Chemother

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Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several betalactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (fT ϾMIC ) was evaluated for ceftazidime (CAZ), and an exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds a 1-mg/liter threshold concentration (fT Ͼ1 mg/liter ) was evaluated for avibactam (AVI). Published CAZ and CZA MIC distributions were incorporated to evaluate cumulative response probabilities. CAZ and AVI were best described by one-compartment models. The values of total body clearance (CL; CAZ CL, 7.53 Ϯ 1.28 liters/h; AVI CL, 12.30 Ϯ 1.96 liters/h) and volume of distribution (V; CAZ V, 18.80 Ϯ 6.54 liters; AVI V, 25.30 Ϯ 4.43 liters) were broadly similar to published values for healthy adults. CZA achieved a PTA (fT ϾMIC , 50%) of Ͼ0.9 for MICs of Յ16 mg/liter. The overall likelihood of a treatment response was 0.82 for CZA, whereas it was 0.42 for CAZ. These data demonstrate improved pharmacodynamics of CZA in comparison with those of CAZ and provide guidance on the optimal dosing of CZA for future studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT02504827.)

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Section: Discussionsupporting

confidence: 79%

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis

Bensman

Wang

Jayne

et al. 2017

Antimicrob Agents Chemother

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“…These breakpoints are based on achievable blood levels of antimicrobials and not levels achievable in the lung, as is the case with aerosolized antimicrobials, where local levels greatly exceed those achievable by systemic administration (7). The converse also applies, where achievable levels in the lung can be less than blood levels (20). It is unfortunate that we are unable to comment on any treatment outcomes based on the recommendations of CFASS, but, that said, feedback from the users of CFASS indicates that they find the extended susceptibility testing results helpful in guiding therapy (16).…”

Section: Discussionmentioning

confidence: 99%

Combination Antimicrobial Susceptibility Testing of Multidrug-Resistant Stenotrophomonas maltophilia from Cystic Fibrosis Patients

Milne

Gould

2012

Antimicrob Agents Chemother

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Stenotrophomonas maltophilia is increasingly being isolated from the respiratory tract of individuals with cystic fibrosis, and, because of its multidrug-resistant nature, the selection of suitable treatment regimens can be problematical. Etest methodology was used to facilitate MIC and antimicrobial combination testing on 80 isolates of S. maltophilia cultured from the respiratory tract of Scottish individuals with cystic fibrosis between 2001 and 2010. The overall rate of susceptibility for the 1,410 MIC tests was 23.1%, and resistance was 68.9%. The most active antimicrobials were minocycline, co-trimoxazole, and doxycycline, with 92.4%, 87.3%, and 58.8% of isolates being susceptible, respectively. Of the 517 combinations, 13.2% were synergistic, with the most synergistic being ticarcillin/clavulanate plus aztreonam (91.7% synergistic), ticarcillin/clavulanate plus colistin (40%), and ticarcillin/clavulanate plus levofloxacin (19.4%). Colistin plus tobramycin was the only antagonistic combination (0.2%). By the median susceptible breakpoint index, the most active combinations were minocycline plus co-trimoxazole (median index, 20), minocycline plus piperacillin-tazobactam (median, 20), and co-trimoxazole plus ceftazidime (median, 16.5). The increasing problem of multidrug resistance in organisms recovered from the respiratory tracts of individuals with cystic fibrosis is not going to go away. Current susceptibility testing methods do not address the slow-growing organisms associated with chronic infection, and interpretive standards are based on achievable blood levels of antimicrobials. Addressing these issues specifically for organisms recovered from the respiratory tracts of individuals with cystic fibrosis should lead to better therapeutic outcomes and improved wellbeing of individuals with cystic fibrosis.

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“…Several data suggest that the use of standard drug dosages result in sub-optimal drug concentrations at the site of infection [41] due to low concentrations of antibiotics at the site of infection [239] and the increased tolerance of biofilms to antibiotics [169][170][171].…”

Section: Therapeutic Strategies To Circumvent These Challengesmentioning

confidence: 99%

Antimicrobial resistance, respiratory tract infections and role of biofilms in lung infections in cystic fibrosis patients

Ciofu

Tolker‐Nielsen

Jensen

et al. 2015

Advanced Drug Delivery Reviews

270

237

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Sputum antibiotic concentrations: Implications for treatment of cystic fibrosis lung infection

Abstract: Key PDIs associated with clinical effectiveness for ceftazidime and tobramycin were not achieved at the site of infection in the lungs of CF patients.

Cited by 55 publications

References 46 publications

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis

Combination Antimicrobial Susceptibility Testing of Multidrug-Resistant Stenotrophomonas maltophilia from Cystic Fibrosis Patients

Antimicrobial resistance, respiratory tract infections and role of biofilms in lung infections in cystic fibrosis patients

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