Pharmacodynamics of tobramycin in patients with cystic fibrosis

Mouton, Johan W.; Jacobs, Nico; Tiddens, Harm A.W.M.; Horrevorts, A. M.

doi:10.1016/j.diagmicrobio.2005.02.011

Cited by 66 publications

(73 citation statements)

References 27 publications

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“…These results compare well with the PK/PD analyses of ceftazidime and Gram-negative microorganisms in the comparator arm of the trial, where %fTϾMIC was also identified as the parameter correlating with outcome in patients (9). To calculate the PK/PD indices, we used the highest MIC encountered, reasoning that outcome would be related to the bacteria with the lowest exposure in case multiple microorganisms were cultured (9,14). The cultures that were used were taken at BL and at EOT.…”

Section: Discussionmentioning

confidence: 76%

Exposure to Ceftobiprole Is Associated with Microbiological Eradication and Clinical Cure in Patients with Nosocomial Pneumonia

Muller

Punt²,

Mouton

2014

Antimicrob Agents Chemother

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dThe percentage of the dosing interval that the non-protein-bound plasma concentration is above the MIC (%fT>MIC) for cephalosporins has been shown to correlate with microbiological outcomes in preclinical studies. However, clinical data are scarce. Using data from a randomized double-blind phase 3 clinical trial, we explored the relationship of ceftobiprole exposure with microbiological and clinical outcomes in patients with nosocomial pneumonia. The individual ceftobiprole exposure was determined for different pharmacokinetic (PK)/pharmacodynamic (PD) indices using individual pharmacokinetic data and a previously published population model. The MICs used in the analysis were the highest MICs for any bacterium cultured at baseline or the end of treatment (EOT). Outcomes were microbiological cure at EOT and clinical cure at test of cure (TOC). Multiple logistic regression (MLR) and classification and regression tree (CART) analyses were applied to determine the relationships among exposure, patient characteristics, and outcomes. MLR indicated that the %fT>MIC of ceftobiprole was the best predictor for both microbiological eradication and clinical cure. CART analysis showed a breakpoint value of 51.1% (n ‫؍‬ 159; P ‫؍‬ 0.0024) for clinical cure, whereas it was 62.2% (n ‫؍‬ 251; P < 0.0001) for microbiological eradication. Other factors also contributed, particularly to clinical outcome. These included the difference between VAP and non-VAP patients, systemic inflammatory response syndrome (SIRS), creatinine clearance, the use of anti-Pseudomonas combination therapy, and Acute Physiology and Chronic Health Evaluation II (APACHE-II) score. There is a strong correlation between microbiological eradication and clinical cure with exposure to ceftobiprole. The %fT>MIC required to result in a favorable clinical outcome is >51% of the dosing interval, which is in line with the values found for microbiological eradication, the comparator ceftazidime, and preclinical models. C eftobiprole, the active moiety of its prodrug ceftobiprole medocaril, is a broad-spectrum cephalosporin active against most Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA), as well as Gram-negative microorganisms. Similar to other ␤-lactams, studies in animals and in vitro pharmacokinetic (PK) models have shown that the percentage of the dosing interval that the maximum concentration of the free, unbound fraction of drug in serum is above the MIC (%fTϾMIC) is the PK/pharmacodynamic (PD) index that best correlates with drug-related response (1). A %fTϾMIC of 60 to 65% of the dosing interval has been identified in mouse infection models as the target of near-maximal bacterial killing, and a %fTϾMIC of 40% best predicted bacteriostasis at 24 h for cephalosporins in general (2-4). These %fTϾMIC values are often regarded as PD targets for drug exposure and as the values on which to base clinical breakpoints, and in general as targets to reach during therapy (5). Whereas data to support the use of these targets in...

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Section: Discussionmentioning

confidence: 76%

Exposure to Ceftobiprole Is Associated with Microbiological Eradication and Clinical Cure in Patients with Nosocomial Pneumonia

Muller

Punt²,

Mouton

2014

Antimicrob Agents Chemother

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“…Evaluations of the pharmacodynamic characteristics of aminoglycosides are scarce. C max /MIC and AUC/ MIC ratios of 8 to 10 and 80 h to 100 h, respectively, are reasonable to predict the likelihood of efficacy in the treatment of nosocomial infections, including respiratory tract infections (217)(218)(219)(220). The most predictive PK/PD efficacy parameter in CF patients was the C max /MIC ratio (221).…”

Section: Preclinical and Clinical Pk/pd Studies In Cf Patientsmentioning

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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“…Presently, clinical decisions on treatment are often based on in vitro susceptibility data (MICs), which only provide information about antibacterial activity at a single time point and potentially miss information on the changes in bacterial population dynamics over time. Drug selections solely based on MIC values may not always correlate to patient outcomes (11). One major reason for the discrepancy may be due to in vitro investigations neglecting the presence of the immune system in patients, which is well known to be significant.…”

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confidence: 98%

Quantitative Impact of Neutrophils on Bacterial Clearance in a Murine Pneumonia Model

Guo

Abdelraouf

Ledesma

et al. 2011

Antimicrob Agents Chemother

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The rapid increase in the prevalence of antibiotic-resistant pathogens is a global problem that has challenged our ability to treat serious infections. Currently, clinical decisions on treatment are often based on in vitro susceptibility data. The role of the immune system in combating bacterial infections is unequivocal, but it is not well captured quantitatively. In this study, the impact of neutrophils on bacterial clearance was quantitatively assessed in a murine pneumonia model. In vitro time-growth studies were performed to determine the growth rate constants of Acinetobacter baumannii ATCC BAA 747 and Pseudomonas aeruginosa PAO1. The absolute neutrophil count in mice resulting from different cyclophosphamide preparatory regimens was determined. The dynamic change of bacterial (A. baumannii BAA 747) burden in mice with graded immunosuppression over 24 h was captured by a mathematical model. The fit to the data was satisfactory (r 2 ‫؍‬ 0.945). The best-fit maximal kill rate (K k ) of the bacterial population by neutrophils was 1.743 h ؊1 , the number of neutrophils necessary for 50% maximal killing was 190.8/l, and the maximal population size was 1.8 ؋ 10 9 CFU/g, respectively. Using these model parameter estimates, the model predictions were subsequently validated by the bacterial burden change of P. aeruginosa PAO1 at 24 h. A simple mathematical model was proposed to quantify the contribution of neutrophils to bacterial clearance and predict the bacterial growth/ suppression in animals. Our results provide a novel framework to link in vitro and in vivo information and may be used to improve clinical treatment of bacterial infections.The rapid increase in the prevalence of antibiotic-resistant pathogens is a global problem that has challenged our ability to treat serious infections. To prevent further spread of multidrug resistance and returning to the preantibiotic era, it is imperative that the current approach to treatment be improved. Presently, clinical decisions on treatment are often based on in vitro susceptibility data (MICs), which only provide information about antibacterial activity at a single time point and potentially miss information on the changes in bacterial population dynamics over time. Drug selections solely based on MIC values may not always correlate to patient outcomes (11). One major reason for the discrepancy may be due to in vitro investigations neglecting the presence of the immune system in patients, which is well known to be significant.The immune system (especially neutrophils) plays an important role in combating bacterial infections. This is best exemplified by patients with neutropenia or after transplantation, who have significantly higher mortality than patients without neutropenia (8, 10, 13). However, the effect of the immune system is not well accounted for when data obtained from in vitro investigations are used to provide guidance for treatment. The overall antimicrobial effect in a patient is the sum of the antibacterial activity from drug therapy and the effect ...

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Pharmacodynamics of tobramycin in patients with cystic fibrosis

Cited by 66 publications

References 27 publications

Exposure to Ceftobiprole Is Associated with Microbiological Eradication and Clinical Cure in Patients with Nosocomial Pneumonia

Exposure to Ceftobiprole Is Associated with Microbiological Eradication and Clinical Cure in Patients with Nosocomial Pneumonia

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

Quantitative Impact of Neutrophils on Bacterial Clearance in a Murine Pneumonia Model

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