Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin

Forrest, Alan; Ballow, Charles H.; Nix, David E.; Birmingham, Mary C.; Schentag, Jerome J.

doi:10.1128/aac.37.5.1065

Cited by 123 publications

(114 citation statements)

References 26 publications

(33 reference statements)

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“…We found that a two-compartment model best described the disposition of ciprofloxacin in our adult CF population. This is similar to the results of Forrest et al, who evaluated the pharmacokinetics of ciprofloxacin in acutely ill, non-CF patients (7).…”

Section: Discussionsupporting

confidence: 79%

Population Pharmacokinetics and Use of Monte Carlo Simulation To Evaluate Currently Recommended Dosing Regimens of Ciprofloxacin in Adult Patients with Cystic Fibrosis

Montgomery¹,

Beringer²,

Aminimanizani³

et al. 2001

Antimicrob Agents Chemother

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Pharmacodynamic data on ciprofloxacin indicate that a target area under the concentration-time curve from 0 to 24 h (AUC 0-24 )/MIC ratio of >125 is necessary to achieve optimal bactericidal activity for the treatment of gram-negative pneumonia. The purpose of this prospective study was to (i) develop a pharmacokinetic (PK) model to be utilized for therapeutic drug monitoring (TDM) of ciprofloxacin and (ii) evaluate current ciprofloxacin dosing regimens for pneumonias in cystic fibrosis (CF) patients. Twelve adult CF patients received a single 400-mg dose of IV ciprofloxacin. Six blood samples were obtained over a 12-h interval. Serum drug concentrations were determined by high-pressure liquid chromotography and were fitted to one-and two-compartment models by using NPEM2. Ciprofloxacin MIC data for Pseudomonas aeruginosa were obtained Acute pulmonary exacerbations requiring antibiotic and airway clearance therapy are the most frequent complication of cystic fibrosis (CF). Acute exacerbations occur as a result of a flare-up of the chronic infection within the lower airways. In this scenario, the therapeutic goals include reduction of bacterial density and improvement of pulmonary function and nutritional status (16). Therefore, the primary therapeutic approach is institution of antimicrobial therapy directed against the most commonly encountered pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae.Ciprofloxacin is a second-generation fluoroquinolone with a broad spectrum of activity. It possesses potent bactericidal activity against P. aeruginosa isolates from CF patients (1, 18). In addition, ciprofloxacin has consistently demonstrated synergistic activity with other antipseudomonal agents against multiple-drug-resistant P. aeruginosa isolates obtained from CF patients (18). With these attributes, it is not surprising that ciprofloxacin is frequently prescribed for the treatment of pulmonary exacerbations in CF patients.The pharmacokinetics of ciprofloxacin have been extensively evaluated in stable CF patients (4,9,11,14,17,20,23). Results of these studies indicate no significant alterations in pharmacokinetics when patients are compared with normal healthy volunteers. In contrast, data on the pharmacokinetics of ciprofloxacin during acute pulmonary exacerbations are limited (2, 21). In addition, none of these studies performed compartmental pharmacokinetic analysis, which would permit dosage individualization for the patient. Studies performed in non-CF patients with nosocomially acquired lower respiratory tract infections demonstrated that optimal clinical and bacteriological outcomes are associated with achievement of specific threshold values of pharmacodynamic variables, such as the area under the concentration time curve from 0 to 24 h (AUC 0-24 )/MIC ratio and peak/MIC ratio (6, 15). Specifically, Forrest et al. demonstrated that optimal clinical and bacteriological responses in non-CF patients with lower respiratory tract infections are associated with the abili...

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Section: Discussionsupporting

confidence: 79%

Population Pharmacokinetics and Use of Monte Carlo Simulation To Evaluate Currently Recommended Dosing Regimens of Ciprofloxacin in Adult Patients with Cystic Fibrosis

Montgomery¹,

Beringer²,

Aminimanizani³

et al. 2001

Antimicrob Agents Chemother

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“…and p.o. studies were then comodelled by iterative two-stage analysis (13,28,30). The maximum likelihood results were used to derive an initial estimate of the population pharmacokinetic model by using a standard two-stage approach.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and bioavailability of fluconazole in patients with AIDS

DeMuria

Forrest

Rich

et al. 1993

Antimicrob Agents Chemother

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Fluconazole pharmacokinetics were evaluated for 10 volunteers with AIDS who had no clinical evidence of gastroenteritis. Single 100-mg intravenous (i.v.) and oral (p.o.) doses were administered in a randomized, crossover design. i.v. doses were delivered by a constant-rate infusion over 30 min. Serum fluconazole concentrations were measured by gas-liquid chromatography. The i.v. and p.o. studies were modelled simultaneously by iterative two-stage analysis, which provided individual parameter estimates and a population pharmacokinetic model. Median areas under the concentration-time curves for i.v. and p.o. studies did not differ (90.6 and 99.3 ,ug/ml. h, respectively). Consistent with this finding, the median fractional bioavailability was 1.1 (range, 0.45 to 1.3), comparable to those in healthy subjects. Serum pharmacokinetics in these AIDS patients were generally similar to published data for healthy volunteers. However, foliowing p.o. dosing, we observed a slightly delayed and highly variable time to maximum concentration in serum (median, 2 h; range, 15 min to 8 h). Data were well described by a linear, two-compartment pharmacokinetic model with first-order absorption and elimination. Repeated-measures analysis ofvariance found no significant differences among any of the pharmacokinetic parameters between i.v. and p.o. studies. On the basis of our findings, we suggest no change in dosage of p.o. fluconazole in patients with AIDS who show no clinical signs of enteropathy.Oral (p.o.) fluconazole is frequently administered to persons with AIDS for the treatment of commonly occurring fungal infections, including oropharyngeal and esophageal candidiasis (31) and cryptococcal meningitis (32). Frequently, AIDS patients have hypochlorhydria (23) and other physiologic and anatomic disturbances of the alimentary tract (17,22,25), although gastroenteral symptoms may be absent. Potentially, these factors could interfere with the overall absorption of p.o. administered agents, alter drug transit time, and influence efficacy (11,29).To our knowledge, the absorption of p.o. fluconazole in patients with AIDS has not been investigated. The recommended dosage of p.o. fluconazole for the treatment of fungal infections in patients with AIDS is based upon pharmacokinetic data derived from healthy volunteers (4,14,21). The objective of this study was to determine the p.o. bioavailability and pharmacokinetics of fluconazole in patients with AIDS.(Results of this investigation were presented at the VIIIth International Conference on AIDS/IIIrd STD World Congress, Amsterdam, The Netherlands, July 1992.) MATERIALS AND METHODSPatients and selection criteria. The study population consisted of ambulatory patients who were served by the Brigham and Women's Hospital and the Harvard Community Health Plan (Boston, Mass.). The study protocol was approved by the institutional review boards for human investigation of both institutions. Written informed consent was obtained from each subject.Volunteers who had AIDS (5) were eligible for the stu...

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“…A 10,000-subject Monte Carlo simulation predicted that the overall attainment of the target exposure for suppression of Pseudomonas resistance was 61.2% for a levofloxacin regimen of 750 mg intravenously daily. To put this into perspective, we performed a similar simulation for ciprofloxacin (another fluoroquinolone antimicrobial) for a regimen of 400 mg IV every 8 hours (27), with a target-exposure attainment of 61.8%. Both simulations were derived from data collected from patients with nosocomial pneumonia.…”

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confidence: 99%

Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy

Jumbe¹,

Louie²,

Leary³

et al. 2003

J. Clin. Invest.

222

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Development and owns stock and stock options. James B. Kahn is an employee of OrthoMcNeil Pharmaceutical and owns stock and stock options. Nonstandard abbreviations used: minimum inhibitory concentration (MIC); Mueller-Hinton II broth (MHB); minimum bactericidal concentration (MBC); area under the concentration time curve (AUC); nonparametric expectation maximization 2 (NPEM2); maximum a posteriori probability (MAP); quinolone resistance-determining region (QRDR).caused by antibiotic-resistant bacteria are more difficult to treat, resulting in excess morbidity and mortality as well as higher health care costs. Therefore, it is imperative to identify ways of suppressing the emergence of antibiotic-resistant mutants.Current preclinical methods for assessing the efficacy of an antimicrobial agent most often evaluate the effect of selected dosages of the compound on the reduction in the total bacterial population at an infection site. The impact of drug pressure on the amplification of the drug-resistant subpopulation is ignored (1-3).For some antibiotic dosages, the drug-susceptible population may be completely replaced with resistant mutants over time. Clinically, this may manifest as the failure of an infection to respond to therapy or a relapse of infection with drug-resistant mutants shortly after a prescribed course of antibiotic therapy is completed.The probability that a resistant subpopulation exists within a predominantly drug-susceptible wildtype population is dependent on the number of organisms at the infection site (total population burden) and the mutational frequency to resistance to The worldwide increase in the prevalence of multi-antibiotic-resistant bacteria has threatened the physician's ability to provide appropriate therapy for infections. The relationship between antimicrobial drug concentration and infecting pathogen population reduction is of primary interest. Using data derived from mice infected with the bacterium Pseudomonas aeruginosa and treated with a fluoroquinolone antibiotic, a mathematical model was developed that described relationships between antimicrobial drug exposures and changes in drug-susceptible and -resistant bacterial subpopulations at an infection site. Dosing regimens and consequent drug exposures that amplify or suppress the emergence of resistant bacterial subpopulations were identified and prospectively validated. Resistant clones selected in vivo by suboptimal regimens were characterized. No mutations were identified in the quinolone resistance-determining regions of gyrA/B or parC/E. However, all resistant clones demonstrated efflux pump overexpression. At base line, MexAB-OprM, MexCD-OprJ, and MexEF-OprN were represented in the drug-resistant population. After 28 hours of therapy, MexCD-OprJ became the predominant pump expressed in the resistant clones. The likelihood of achieving resistance-suppression exposure in humans with a clinically prescribed antibiotic dose was determined. The methods developed in this study provide insight regarding how mathematical m...

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Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin

Cited by 123 publications

References 26 publications

Population Pharmacokinetics and Use of Monte Carlo Simulation To Evaluate Currently Recommended Dosing Regimens of Ciprofloxacin in Adult Patients with Cystic Fibrosis

Population Pharmacokinetics and Use of Monte Carlo Simulation To Evaluate Currently Recommended Dosing Regimens of Ciprofloxacin in Adult Patients with Cystic Fibrosis

Pharmacokinetics and bioavailability of fluconazole in patients with AIDS

Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy

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