|Home | About | Journals | Submit | Contact Us | Français|
We evaluated the pharmacokinetic profile of ciprofloxacin and its penetration into bronchial secretions of critically ill patients with chronic obstructive pulmonary disease (COPD). Twenty-five mechanically ventilated patients with severe COPD who were suffering from an acute, infectious exacerbation were included in this prospective, open-label study. All subjects received a 1-hour intravenous infusion of 400 mg ciprofloxacin every 8 h. Serial blood and bronchial secretion samples were obtained at steady state, and concentrations were determined using high-performance liquid chromatography. The pharmacodynamic parameters that are associated with the efficacy of fluoroquinolones against Gram-negative pathogens were also calculated. The mean peak (maximum) concentration (Cmax) and trough (minimum) concentration in plasma were 5.37 ± 1.57 and 1 ± 0.53 mg/liter, respectively. Mean values for volume of distribution, clearance, half-life, and area under the curve from 0 to 24 h (AUC0–24) were 169.87 ± 84.11 liters, 26.96 ± 8.86 liters/h, 5.35 ± 2.21 h, and 47.41 ± 17.02 mg · h/liter, respectively. In bronchial secretions, a mean Cmax of 3.08 ± 1.21 mg/liter was achieved in 3.12 ± 1.01 h, and the penetration ratio was 1.16 ± 0.59. The target of AUC0–24/MIC of ≥125 was attained in all patients, in the majority of them (76%), and in none at MICs of 0.125, 0.25, and 1 μg/ml, respectively. Slightly better results were obtained for the ratio Cmax/MIC of ≥10. In conclusion, ciprofloxacin demonstrates excellent penetration into bronchial secretions. There is wide interindividual variability in its pharmacokinetic parameters in critically ill COPD patients and inadequate pharmacodynamic exposure against bacteria with MICs of ≥0.5 μg/ml.
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease which is characterized by airflow limitation and is associated with an abnormal inflammatory response of the lung to noxious particles or gases (25). COPD is the fourth leading cause of death worldwide and a major cause of chronic morbidity (35). The prevalence of the disease in adults aged ≥40 years is about 9 to 10%, according to a recent meta-analysis (15). COPD patients may experience frequent and debilitating exacerbations of their disease. Bacterial infections have generally been considered the leading cause of these exacerbations. In some patients, mostly those with severe airflow obstruction, respiratory failure may occur and mechanical ventilation is sometimes necessary. Gram-negative enteric bacilli and Pseudomonas spp. seem to have a prominent role in these severe exacerbations (11, 31).
According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the European Respiratory Society guidelines for the management of adult lower respiratory tract infections, and the Canadian guidelines for the management of acute exacerbations of chronic bronchitis, ciprofloxacin is the antibiotic of choice for the treatment of patients with severe exacerbations of COPD (25, 36, 2). These patients have seriously impaired lung function, they possess risk factors for Pseudomonas aeruginosa infection, and they often require mechanical ventilation. Ciprofloxacin, a broad-spectrum fluoroquinolone, is active against a wide variety of Gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, Moraxella catarrhalis, and Enterobacter aerogenes, and is also active against some Gram-positive cocci (5). One of its prominent characteristics is a high level of activity against P. aeruginosa, although a significant percentage of resistant strains continues to emerge (21).
Antibiotic penetration into the site of infection is critical in order to achieve a favorable clinical outcome. Since in COPD patients the infection develops within the airway lumen, it is important to know the concentrations that are achieved in bronchial secretions (1). Despite numerous previous studies, the pharmacokinetic profile of ciprofloxacin has not been studied in mechanically ventilated COPD patients, who usually produce large quantities of purulent secretions. Moreover, the previously used dose of 800 mg per day has been increased to 1,200 mg per day in critically ill patients because of the observed inadequate drug levels and suboptimal pharmacodynamic exposure (23, 34). Optimizing antimicrobial therapy in patients hospitalized in an intensive care unit (ICU) can be difficult due to various pathophysiological changes that lead to altered and highly variable drug pharmacokinetics (26). Only a few data for this dosing regimen are available from clinical studies. The purpose of this study was to evaluate the pharmacokinetic parameters of ciprofloxacin, administered at a dosage of 400 mg intravenously every 8 h (q8h), and its penetration into bronchial secretions of mechanically ventilated COPD patients in the ICU.
This study was designed as a prospective, open-label study, which took place in a respiratory failure unit and in a general ICU of G. Papanikolaou Hospital in Thessaloniki, Greece. It was approved by the Institutional Review Board of the hospital. The study period was from September 2008 to November 2009. Informed consent was obtained from the patients or, in the vast majority of the cases, their legal representatives.
Patients were eligible for enrollment in the study if they had a history of COPD and were experiencing at the time of enrollment an acute exacerbation which was attributed to an infection and for which they received ciprofloxacin. An exacerbation was defined as the presence of at least one of the following: a change in the patient's baseline dyspnea, cough, or sputum that led to a change in management (7). Patients received antibiotics if they had increased dyspnea, sputum volume, and sputum purulence or if they had two of the above symptoms and increased purulence of sputum was one of them (25). Furthermore, at their admission to the ICU, patients had to have signs of infection such as fever (body temperature > 38°C), tachycardia (heart rate > 90/min), and a white blood cell count of >12,000/mm3 or <4,000/mm3. All exacerbations were considered severe due to the presence of acute respiratory failure and required the patient to undergo invasive mechanical ventilation.
A complete medical history and laboratory test results, including complete blood cell counts, serum glucose and electrolytes, liver function tests, total proteins and albumin, and serum creatinine and urine analyses, were recorded before the study. Exclusion criteria were as follows: a history of allergy to fluoroquinolones; renal insufficiency, defined as a creatinine clearance (CLCR) of 30 ml/min or less, as calculated by the Cockroft-Gault equation (8); hepatic impairment, defined as a Child-Pugh score of B or C; a history of convulsions; and concomitant use of theophylline.
Ciprofloxacin was prescribed empirically to the patients who had risk factors for P. aeruginosa infection, such as recent hospitalization; frequent (more than four courses per year) or recent (in the last 3 months) administration of antibiotics; severe disease, defined as forced expiratory volume in 1 s (FEV1) of <30% predicted; and previous isolation of P. aeruginosa during an exacerbation or colonization by P. aeruginosa (36). Patients were given ciprofloxacin intravenously at a dosage of 400 mg every 8 h by infusion over 1 h via a central venous line.
The study was conducted on the second day of therapy, when the drug was expected to be at steady state. Blood samples were obtained via an arterial catheter just prior to the administration of the dose (time zero) and at the following time points postdosing: 1 h (at the end of the infusion), 70, 80, and 90 min, and 2, 3, 4, 6, and 8 h (just before administration of the next dose). Plasma was separated by centrifugation. Samples of bronchial secretions were obtained via a mucus aspirator through the endotracheal tube. They were collected before the administration of the dose (time zero), at 1 h (at the end of the infusion) and 2, 4, 6, and 8 h (before the administration of the next dose). Bronchial secretions were homogenized and emulsified with an ultrasonic processor for 1 min (VCX-130; Sonics & Materials Inc., Newton, CT). All samples were stored at −20°C until analyzed.
Ciprofloxacin concentrations in plasma and bronchial secretions were determined using high-performance liquid chromatography (HPLC) with fluorescence detection according to a previously described method with modifications (16). The HPLC system (model 1100 series; Agilent Technology, Waldbronn, Germany) utilized a Nucleosil 100C18 analytical column (particle size, 5 μm; 250 by 4.6 mm) protected by a guard column (Nucleosil 100C18; particle size, 5 μm; 20 by 4.6 mm). The detector was set at an excitation wavelength of 278 nm and at an emission wavelength of 415 nm. The mobile phase consisted of phosphate buffer and acetonitrile at 87:13 (vol/vol). Pipemidic acid was used as the internal standard. The flow rate was 2 ml/min, and the run time was 12 min.
Coefficients of determination (r2) for ciprofloxacin over the standard curve concentrations of 0.05 to 10 mg/liter for plasma and of 0.05 to 6 mg/liter for bronchial secretions were 0.999 for the entire study. Intraday and interday coefficients of variation ranged from 1.7 to 3% and 0.99 to 3.42%, respectively, for ciprofloxacin plasma samples and from 1.09 to 3.22% and 1.16 to 2.15%, respectively, for bronchial secretion samples. The recovery of ciprofloxacin in plasma was 100 to 102.4%, and that in bronchial secretions was 93 to 98.9%.
Plasma ciprofloxacin concentrations were plotted against time, and the pharmacokinetic parameters were estimated by compartmental analysis using the WinNonlin software program (version 3.0; Pharsight Corporation, Mountain View, CA). A two-compartment model with first-order elimination and no lag time was used, and the goodness of fit of the model was determined by using the Akaike and Schwartz criteria, as well as the correlation between the observed and the calculated concentrations. The peak (maximum) concentration (Cmax) in plasma was at the end of the infusion, and the trough (minimum) concentration (Cmin) in plasma was just before the administration of the next dose. In bronchial secretions, Cmax and the time to reach Cmax were obtained observationally from individual concentration-time data. All concentrations in both matrices were total drug concentrations. The area under the curve from 0 to 8 h (AUC0–8) was determined by the trapezoidal rule. AUC0–24 was calculated by multiplying AUC0–8 by 3. The penetration ratio for each patient was obtained by dividing the AUC0–24 for bronchial secretions by the AUC0–24 for plasma.
Descriptive and summary statistics were used. All results are presented as means ± standard deviations unless otherwise noted.
Twenty-five patients (20 males and 5 females) were included in the study. Their characteristics are shown in Table 1. All of the patients had a history of severe COPD according to the spirometric classification of GOLD (FEV1/forced vital capacity, <0.70; FEV1, between 30 and 49% predicted) (25). The patients had an average age of 70.1 ± 8.3 years and were severely ill (admission Acute Physiology and Chronic Health Evaluation II [APACHE II] score, 21 ± 6; admission Simplified Acute Physiology Score [SAPS II], 49 ± 12). Twelve patients improved and were finally discharged from the hospital, while the other 13 died mainly because of severe sepsis and multiorgan dysfunction syndrome, complications that developed later during their ICU stay. No adverse effects of the antibiotic were observed in our study group.
The pharmacokinetic parameters of ciprofloxacin are summarized in Table 2. The mean peak and trough concentrations in plasma were 5.37 ± 1.57 and 1 ± 0.53 mg/liter, respectively. There was a large variability in the pharmacokinetic data, especially in the volume of distribution at steady state (Vss), which showed a 7-fold variation. Similarly, clearance (CL) ranged from 13 to 42.72 liters/h, and the elimination half-life (t1/2) was as short as 3.07 h and as long as 12.11 h. Calculation of Vss, CL, and t1/2 was performed by a compartmental method, as it was described in the pharmacokinetic analysis.
In bronchial secretions, the mean Cmax was 3.08 ± 1.21 mg/liter, and it was observed 3.12 ± 1.01 h after the start of the infusion. The mean Cmin was found to be 1.34 ± 0.52 mg/liter. A time delay in the penetration of ciprofloxacin into bronchial secretions was noted. This resulted in the lower peak concentrations in this matrix compared to plasma, even though the AUC values were roughly equivalent. The antibiotic penetrated well into bronchial secretions, achieving maximum concentrations that were 60% ± 25% of those in plasma and a penetration ratio of 1.16 ± 0.59. Fifteen patients demonstrated penetration equal to or even more than 100%. Moreover, in 23 patients, the concentrations in bronchial secretions remained above 0.5 mg/liter for the whole dosing interval, while in the other 2 they were lower (≥0.25 mg/liter). The concentration-time profiles of ciprofloxacin in plasma and in bronchial secretions are presented in Fig. 1 and and2,2, respectively.
We also calculated the AUC0–24/MIC and Cmax/MIC ratios in plasma, which are the pharmacodynamic parameters that characterize the fluoroquinolones, even though in reality the free AUC0–24/MIC and free Cmax/MIC ratios are the true parameters. Since ciprofloxacin is the antibiotic of choice in these patients mainly because of its activity against P. aeruginosa, we attempted to evaluate its efficacy against this particular microorganism. The various MICs (0.125, 0.25, 0.5, and 1 μg/ml) were used on the basis of its susceptibility MIC breakpoint, which is 1 μg/ml according to the Clinical and Laboratory Standards Institute. Previous studies have demonstrated that an AUC0–24/MIC ratio of ≥125 and a Cmax/MIC ratio of ≥10 are related to optimum clinical and microbiological outcomes (12, 10). All patients had an AUC0–24/MIC ratio of 125 or more at the lowest MIC (0.125 μg/ml) but none at the highest MIC (1 μg/ml). This goal was achieved in 19 patients (76%) and in 4 patients (16%) when the MICs were 0.25 and 0.5 μg/ml, respectively. Regarding the Cmax/MIC ratio, it was equal to or greater than 10 in all patients when MICs were 0.125 and 0.25 μg/ml and in 16 patients (64%) and in 1 patient (4%) when MICs were 0.5 and 1 μg/ml, respectively. On the basis of the microbiological data of our hospital, only 42% of P. aeruginosa strains had MICs of ≤0.25 μg/ml. Accordingly, the pharmacodynamic target would be attained in less than half of the strains.
Ciprofloxacin has been found to be one of the most widely used appropriate antibiotics for the treatment of patients with severe acute exacerbations of COPD in terms of predicted clinical efficacy (6). Some of these patients are critically ill and require hospitalization in the ICU. Immediate and adequate antibiotic treatment in terms of spectrum of activity and of dose and frequency of administration is of paramount importance, since these severe exacerbations are mostly due to infections, which contribute considerably to the morbidity and mortality of the disease. Despite appropriate standard dosage regimens, failure of the antimicrobial treatment as well as development of resistance may occur because antimicrobial activity in critically ill patients is characterized by altered pharmacokinetic properties due to the underlying pathophysiological conditions (26, 32). Optimization of antibiotic therapy on the basis of the pharmacokinetic/pharmacodynamic characteristics of antibiotics in these patients should therefore be a priority.
The results of our study show that there is significant interindividual variability in the pharmacokinetic data for ciprofloxacin, administered at 400 mg q8h, in critically ill COPD patients. This can be attributed to the fact that our study population consisted of severely ill patients and some of them presented a mild impairment of their renal function. In particular, two patients demonstrated prolonged half-lives (10.58 and 12.11 h). One of them had the lowest observed CL due to a low CLCR, and the other one had the largest observed Vss. In critical illness, the Vss is altered and in most cases increased, as it was shown in our study too (28).
Similar variability has been noted in other clinical studies in ICU patients. Lipman et al. studied the pharmacokinetic profile of high-dose ciprofloxacin in severe sepsis and observed very wide ranges of CL and Vss (20). Compared to the present study, the mean Cmax in their study was higher (6.68 mg/liter) and the t1/2 was shorter (3.2 h), while the AUC0–8 was similar. Another study that included burn patients who were being treated with the same dose of the antibiotic reported similar results, except for a lower Cmax (4.2 mg/liter) (13). Shah et al. investigated the effect of age and gender on the pharmacokinetics of high-dose ciprofloxacin, and they found that elderly people exhibited a higher Cmax (6.83 mg/liter) and lower CL (21 liters/h) than the young (30). Our patients, who were also elderly, presented values of AUC and t1/2 that were closer to those observed in this study but higher values of CL and Vss. Finally, the results of another healthy volunteer study were closer to ours, with the exception of a lower AUC (19).
One other important aspect of the adequacy of antibiotic therapy is the drug concentrations at the site of infection, which have been shown to correlate with clinical outcome (9, 33). The bacteria that are responsible for an infective exacerbation of COPD most often reside within the lumen, so the levels of an antibiotic achieved in sputum and in bronchial secretions may be the best predictor of therapeutic efficacy (1). The results of our study indicate an excellent penetration of ciprofloxacin in bronchial secretions of intubated COPD patients. The penetration ratio was 1.16 ± 0.59, and most of the patients exhibited a ratio of ≥1. The variability that has been observed can be attributed to differences between patients concerning the endobronchial elimination of the antibiotic, the accumulation of secretions for some time, and the possibility of contamination with small quantities of blood due to airway trauma during the aspiration, as has been pointed out by other investigators too (1, 33).
Other investigators have also examined the penetration of ciprofloxacin in the respiratory tract. A study done in mechanically ventilated patients with nosocomial bronchopneumonia, who were being treated with 200 mg of ciprofloxacin q12h, showed that its penetration was 55 to 60% (27). This ratio ranged from 0.79 to 1.11, much closer to the value that we observed in a previous study (4). Our results are in total agreement with those of another study, which demonstrated that the penetration ratio of orally administered ciprofloxacin in patients with an acute exacerbation of chronic bronchitis is 1 ± 0.5 and that it presents substantial interpatient differences (3).
In cases of pneumonia, on the other hand, the infection develops in the alveolar spaces and in the pulmonary interstitium, so the epithelial lining fluid (ELF) and the alveolar macrophages (AM) are the representative sites of infection (1, 33). It has been shown that ciprofloxacin achieves high concentrations in both sites, mainly in AM. Mean steady-state concentrations of ciprofloxacin at 4 h after administration were 1.9 ± 0.9 μg/ml in ELF and 34.9 ± 23.2 μg/ml in AM of healthy volunteers, who underwent bronchoscopy and bronchoalveolar lavage (BAL) (14). In patients, peak levels of the antibiotic were attained in AM (7.6 ± 1.7 mg/liter) at 5 h after administration of a single oral dose and in ELF (2.13 ± 0.91 mg/liter) at 2.5 h (29). It should be noted that some patients with very severe exacerbations of COPD may actually have pneumonia, in which case penetration of ciprofloxacin into BAL fluid would be most important for efficacy. In our study, though, we did not include any patient with a clinical and radiological diagnosis of pneumonia superimposed on COPD.
Fluoroquinolones are concentration-dependent antibiotics. The pharmacodynamic thresholds associated with efficacy for this class of antibiotics are a Cmax/MIC ratio of 10 to 12 and an AUC0–24/MIC ratio of 125 or more against Gram-negative bacteria and an AUC0–24/MIC ratio of 30 or more against Gram-positive bacteria such as Streptococcus pneumoniae (10, 24, 12, 18). Our study demonstrates an adequate pharmacodynamic exposure only against fully susceptible microorganisms. The AUC0–24/MIC target was achieved in all patients only at a MIC of 0.125 μg/ml and in the majority of them (76%) at a MIC of 0.25 μg/ml. In contrast, when a MIC of 1 μg/ml was evaluated, the pharmacodynamic target was not attained in any patient. Slightly better results were obtained when the pharmacodynamic target Cmax/MIC was examined. Pseudomonas aeruginosa is of special concern in the treatment of severe, acute exacerbations of COPD, as it requires specific antibiotic therapy and eradication is problematic or even impossible. Our local microbiological data combined with the pharmacokinetic/pharmacodynamic results of our study suggest that ciprofloxacin would be efficient against less than half of the strains of this Gram-negative pathogen in our hospital.
Similar conclusions regarding the pharmacokinetic/pharmacodynamic potency of ciprofloxacin at the high dose of 400 mg q8h were also drawn from other studies. In burn patients, only 63% of them achieved an AUC0–24/MIC ratio of 125 for bacteria with a MIC of 0.25 μg/ml (13). A study evaluating ciprofloxacin dosing for P. aeruginosa infection by the use of Monte Carlo simulation demonstrated that the probabilities of target attainment were 0.77 and 0 against isolates with MICs of 0.25 μg/ml and 1 μg/ml, respectively. Likewise, the probability of cure was low at the higher MICs (37). Monte Carlo simulation was also performed in cystic fibrosis patients and showed that only 60% of them would be expected to achieve the targeted AUC0–24/MIC ratio at a MIC of 0.5 μg/ml when they were receiving ciprofloxacin doses of 400 mg q8h. The results of this study supported the consideration of a clinical breakpoint for P. aeruginosa of <0.5 μg/ml (22). Finally, data from the OPTAMA program revealed that ciprofloxacin achieved the lowest target attainment against all bacteria compared to the other antibiotics. In particular, the probability of target attainment was 59% against P. aeruginosa when the highest dosing regimen was used (17).
In conclusion, the pharmacokinetic profile of ciprofloxacin in critically ill COPD patients who are under mechanical ventilation is characterized by wide variability. The antibiotic exhibits excellent penetration into bronchial secretions, and therefore, it is considered a good choice for the treatment of infectious exacerbations of COPD. However, when ciprofloxacin is administered at the currently recommended dose of 400 mg q8h, an adequate pharmacodynamic exposure may be ensured only against bacteria with MICs of ≤0.25 μg/ml. Therefore, combination therapy is probably the best choice for the treatment of pathogens with higher MICs, such as P. aeruginosa. The reevaluation of the susceptibility breakpoint for ciprofloxacin against P. aeruginosa that has been proposed by other investigators could also be considered. Finally, the institution of therapeutic drug monitoring for individualizing antimicrobial dosing in the ICU appears to be necessary in order to optimize efficacy and to prevent the development of resistance.
Published ahead of print on 13 June 2011.