Pharmacokinetics of Continuous Infusion Beta-Lactams in the Treatment of Acute Pulmonary Exacerbations in Adult Cystic Fibrosis Patients (original) (raw)
Related papers
F1000Research
Background: Cystic fibrosis (CF) is associated with frequent pulmonary exacerbations which increase the mortality risk. Therefore, most CF patients are chronically colonized with respiratory pathogens, the most common being Pseudomonas aeruginosa. Multidrug-resistant organisms are a major problem in CF patients. It’s been hypothesized that continuous-infusion antipseudomonal beta-lactam therapy in CF maintains serum concentrations above the minimum inhibitory concentration of susceptible strains and is more likely than intermittent infusion to achieve optimal pharmacodynamic targets for some intermediate and resistant strains of P. aeruginosa. The most extensively studied antibiotic for continuous-infusion protocol in CF is ceftazidime, which has been shown to improve lung function (forced expiratory volume in 1 second and forced vital capacity) and to increase pulmonary exacerbation free time. There have been no studies to evaluate the cost effectiveness or impact on quality of lif...
The pharmacokinetics of antibiotics in cystic fibrosis
Expert Opinion on Drug Metabolism & Toxicology, 2020
Introduction: Dosing of antibiotics in people with cystic fibrosis (CF) is challenging, due to altered pharmacokinetics, difficulty of lung tissue penetration, and increasing presence of antimicrobial resistance. Areas covered: The purpose of this work is to critically review original data as well as previous reviews and guidelines on pharmacokinetics of systemic and inhaled antibiotics in CF, with the aim to propose strategies for optimization of antibacterial therapy in both children and adults with CF. Expert opinion: For systemic antibiotics, absorption is comparable in CF patients and non-CF controls. The volume of distribution (Vd) of most antibiotics is similar between people with CF with normal body composition and healthy individuals. However, there are a few exceptions, like cefotiam and tobramycin. Many antibiotic class-dependent changes in drug metabolism and excretion are reported, with an increased total body clearance for ß-lactam antibiotics, aminoglycosides, fluoroquinolones, and trimethoprim. We, therefore, recommend following class-specific guidelines for CF, mostly resulting in higher dosages per kg bodyweight in CF compared to non-CF controls. Higher local antibiotic concentrations in the airways can be obtained by inhalation therapy, with which eradication of bacteria may be achieved while minimizing systemic exposure and risk of toxicity.
Authorea (Authorea), 2022
Background Acute pulmonary exacerbation (APE) in cystic fibrosis patients is frequent and associated with a decline in pulmonary function, quality of life and survival. Tobramycin is often used in regimens requiring activity against Pseudomonas aeruginosa, however, an important number of centers do not use official dosing recommendation. The current dosing strategy may be suboptimal. Methods This retrospective cohort analysis was performed on all adult cystic fibrosis patients that were admitted at a tertiary care facility for treatment of APE and with tobramycin between January 2015 and December 2019. The primary objective was to evaluate the predictive performance of previously published pharmacokinetic (PK) models and, secondly, to evaluate potential factors that impact clinical outcomes. Clinical outcomes were only evaluated in a subgroup of patients with cultures positive for P. aeruginosa. Results A total of 202 APEs from 51 patients were included in the PK analysis. Two population PK models were assessed and failed to fit our data. In all, 109 APEs from 32 patients were included in the clinical analysis. Factors that significantly impacted clinical outcome were the number of prior APE and concomitant antibiotics. Clinical success rate for regimens containing at least one active agent against P. aeruginosa according to its susceptibility was 67%. Conclusion Population PK models evaluated in this study cannot be used to perform simulations. A new model must be developed for our population. In patients positive for P. aeruginosa, Ceftazidime in combination to tobramycin may be a superior regimen. APE history remains predictive for outcomes in adult CF patients treated for an APE.
Antimicrobial Agents and Chemotherapy, 2000
Once-daily administration of aminoglycosides is routinely used in many institutions. However, comparative efficacy data for patients with cystic fibrosis (CF) are lacking. The purpose of the present study was to compare the predicted pharmacodynamic activity of tobramycin at 10 mg/kg of body weight/day administered every 24 h (q24h), q12h, and q8h. Pharmacokinetic (PK) data were derived from analysis of data on the drug concentration in sera from 60 adult CF patients. Individual maximum a posteriori probability Bayesian PK parameter values were used to construct serum concentration-versus-time curves and to determine various indices (peak concentration/MIC ratio [peak/MIC], area under the concentration-time curve/MIC ratio [AUC/MIC], and time that the concentration was less than the MIC [T<MIC]) for the three regimens described above. MICs of 1, 2, and 4 g/ml for Pseudomonas aeruginosa were assumed in the simulations. Irrespective of the MIC, significantly lower peak/MIC but shorter T<MIC were noted when regimens of q8h versus q12h (P < 0.001), q8h versus q24h (P < 0.001), and q12h versus q24h (P < 0.001) were compared. This analysis suggests that the potential benefit of achieving a greater peak/MIC with once-daily aminoglycoside administration may be offset by the significantly greater T<MIC in CF patients compared with that achieved with multiple-dailydosing regimens. Clinical trials are necessary to determine if once daily aminoglycoside administration is efficacious in the CF population before its routine use can be recommended.
Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis
Pharmacy world & science : PWS, 1998
The disposition of many drugs in cystic fibrosis is abnormal compared with healthy individuals. In general, changes include an increased volume of distribution expressed in liters per kg bodyweight for highly hydrophilic drugs such as aminoglycosides, and, to a lesser extent, for penicillins and cephalosporins, together with an increased total body clearance. The main reason for the increased volume of distribution is the increased amount of lean tissue per kg bodyweight, since patients with CF are generally undernourished and have a paucity of adipose tissue. The reason for the increased renal clearance is less clear. Increased glomerular filtration and tubular secretion have been observed. Protein binding generally is unaltered in CF. The fluorquinolones and vancomycin show no altered pharmacokinetics in CF although gastro-intestinal absorption may be delayed for fluorquinolones. Sulphamethoxazole shows increased clearance due to an increased acetylation and, in the case of trimet...
Infection, 1987
In this review we analyzed the pharmacokinetic basis for high dose treatment with antibiotics of patients with cystic fibrosis. Both our results and those from other well designed pharmacokinetic studies do not support the view that low blood levels of antibacterials are a common feature of CF. We were unable to detect a decrease in absorption, nor could we find evidence for enhanced elimination of antibacterials in CF. Both these factors have been considered responsible for reducing the plasma (and tissue) levels of antibiotics. Most recent studies on kidney function are in agreement with these findings, since neither inulin nor creatinine clearance differ between CF-patients and healthy volunteers. In contrast to previous discussion, the volume of distribution (Vdss) was not elevated for any compound. The rational of weight correction of volume terms like Vdss or total clearance has never been clearly demonstrated and should therefore not be used without prior proof of relevance. Since the variability of pharmacokinetic parameters of antibiotics in CF-patients may be considerable, we suggest that a dose increase of 20–30% may be justified, but cannot agree with two to fourfold increases in dosage as previously proposed and applied in many CF-centers. Until more findings become available for non-adult CF-patients, these conclusions are only valid for adult CF-patients. In dieser Übersichtsarbeit wurde von uns die Grundlage der Hochdosierungstherapie von Antibiotika bei Mukoviszidose kritisch analysiert. Wir verwendeten sowohl Daten aus der Literatur als auch eigene Ergebnisse. Weder die Literaturdaten, die von uns geforderte Kriterien für Vergleichbarkeit erfüllen, noch unsere eigenen Daten haben Hinweise für generell niedrige Plasmaspiegel von Antibiotoka bei Mukoviszidose-Patienten ergeben. Wir haben außerdem nicht zeigen können, daß die Resorption verringert oder die Elimination beschleunigt ist. Beides würde die Plasma-(Gewebs-) Spiegel von Antibiotika erniedrigen. Neuere Untersuchungen zur Nierenfunktion bestätigen diese Ergebnisse, da sich weder die Inulin- noch die Kreatinin-Clearance von CF-Patienten und Gesunden unterschied. Auch die Verteilungsvolumina der Antibiotika waren nicht erhöht, wie das oft diskutiert worden war. Wir haben außerdem die Grundlagen für die oft praktizierte Gewichtskorrektur von Volumenparametern wie Cltot oder Vdss analysiert und sind zu dem Ergebnis gekommen, daß man nicht ungeprüft annehmen kann, daß eine Gewichtskorrektur dieser Volumenparameter für jede Substanz sinnvoll ist. Um die jedoch vorhandene beträchtliche Variabilität der pharmakokinetischen Parameter von Antibiotika bei Mukoviszidose-Patienten ausgleichen zu können, schlagen wir eine Dosiserhöhung um 20 bis 30% vor. Eine Dosiserhöhung um das Zwei- bis Vierfache, wie bisher vorgeschlagen und in vielen CF-Zentren durchgeführt, ist jedoch nach unserer Ansicht nicht gerechtfertigt. Bevor nicht ähnliche Untersuchungen auch bei nicht-erwachsenen CF-Patienten vorliegen, gelten die hier gemachten Dosierungsvorschläge nur für erwachsene Mukoviszidose-Patienten.