Colistin In Patients Research Articles

Effectiveness of treatment with nebulized colistin in patients with COPD.

ObjectivesTo analyze whether the introduction of nebulized colistin in patients with chronic obstructive pulmonary disease (COPD) and infection with Pseudomonas aeruginosa (PA) is associated with a decrease of the number and duration of severe exacerbations.Materials and methodsThirty six patients with COPD and infection with PA treated with nebulized colistin attending a day hospital during a 5-year (January 2010–December 2014) period were prospectively included. Repeated-measures t-tests were used to assess whether the introduction of colistin was associated with changes in the number of exacerbations or the length of the hospitalizations, comparing for each patient the year prior to the introduction of colistin with the year after.ResultsAfter the introduction of colistin, the number of admissions decreased from 2.0 to 0.9 per individual year (P=0.0007), and hospitalizations were shorter (23.3 vs 10.9 days, P=0.00005). These results persisted when patients with and without bronchiectasis or with and without persistence of Pseudomonas were separately analyzed. No pre–post differences were detected in the number of exacerbations not requiring admission.ConclusionNebulized colistin seems associated with a strong decrease in the number and duration of hospitalizations due to exacerbation in patients with COPD and infection with PA. Clinical trials with a larger number of patients are needed in order to confirm these results.

Impact of colistin-initiation delay on mortality of ventilator-associated pneumonia caused by A. baumannii.

There has been increased incidence and high mortality in cases with ventilator-associated pneumonia (VAP) caused by colistin-only-susceptible Acinetobacter baumannii (COS-AB). Colistin has emerged as a therapeutic option for VAP caused by multidrug-resistant Gram-negative organisms including COS-AB. A retrospective study was conducted to examine the impact of early versus late initiation of colistin on 30-day mortality of critically ill patients with VAP caused by COS-AB. Critically ill patients with VAP caused by COS-AB who received colistin were enrolled. The receiver operating characteristic (ROC) curve was used to identify the temporal breakpoint that maximized the difference in 30-day mortality. A total of 56 patients (34 men and 22 women) were included in the study. About 86% of all cases were late-onset VAP. The 30-day mortality was 46.4%. The rate was higher among patients with admission Acute Physiology and Chronic Health Evaluation II (APACHE II) score > 18 and patients with a delay of more than four days in initiating colistin treatment. The mortality rate was 26.9% among patients with treatment delay of four or fewer days and 63.3% for patients with a treatment delay of more than four days. A delay of four days or more in initiating colistin in patients with VAP caused by COS-AB significantly increases mortality. Colistin should be considered in the empirical protocols in late-onset VAP cases when COS-AB is highly suspected.

Updated US and European Dose Recommendations for Intravenous Colistin: How Do They Perform?

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved updated dose recommendations for intravenous colistin in patients with various degrees of renal function. We assessed the recommendations in relation to their ability to achieve clinically relevant plasma colistin concentrations. Pharmacokinetic data from 162 adult critically ill patients (creatinine clearance range, 5.4-211 mL/min) were used to determine the average steady-state plasma colistin concentration (Css,avg) that would be achieved if each patient received the FDA or EMA dose. Target attainment rates for FDA- and EMA-approved daily doses to achieve colistin Css,avg of ≥0.5, ≥1, ≥2, and ≥4 mg/L were determined for each creatinine clearance category (≥80 mL/min, 50 to <80 mL/min, 30 to <50 mL/min, and <30 mL/min). For creatinine clearance <30 mL/min, 100% of patients receiving the EMA dose achieved a colistin Css,avg ≥1 mg/L, but the attainment rate was as low as 53.1% for patients receiving the FDA-approved dose. For colistin Css,avg ≥2 mg/L, the attainment rates were 87.5% with the EMA dose but only 6.3%-34.4% in patients receiving the FDA dose. Differences in attainment rates for a colistin Css,avg of ≥2 mg/L and ≥4 mg/L extended to patients with creatinine clearance 30 to <50 mL/min. For patients with creatinine clearance ≥80 mL/min, only approximately 65%-75% of patients achieved a colistin Css,avg of ≥1 mg/L with either set of recommendations. The study highlights important differences between the FDA- and EMA-approved dose recommendations and informs the setting of clinical breakpoints. NCT00235690.

Systemic absorption of nasally administered tobramycin and colistin in patients with cystic fibrosis.

In cystic fibrosis (CF) patients the paranasal sinuses can constitute a niche for bacteria, which can migrate to the lungs. Nasal administration of antibiotics may be effective, but safety of this treatment has to be established first. The objective of this study was to investigate the systemic absorption of nasally administered tobramycin, colistin (administered as colistin sulfomethate sodium; CMS) and a combination of both drugs using systemic absorption as surrogate for safety. In addition, tolerability of the nasal irrigations was examined. Ten adult CF patients performed three different nasal irrigations: 300 mg of tobramycin; 160 mg of CMS; and 300 mg of tobramycin combined with 160 mg of CMS. Serum concentrations of tobramycin and colistin A and B (the main components of colistin) were analysed. Tolerability was measured using a visual analogue scale. Dutch Trial Register: NTR 4008. Following the tobramycin and the combined irrigation, only two patients had detectable tobramycin serum levels, with the highest being 0.054 mg/L. Serum levels of colistin A and B were not detectable. All three nasal irrigation solutions were well tolerated with a higher tolerability for CMS compared with tobramycin. Nasal irrigations with tobramycin, CMS and a combination of tobramycin and CMS resulted in safe serum levels and were well tolerated.

Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection.

Chronic infection with Pseudomonas aeruginosa is associated with an increased exacerbation frequency, a more rapid decline in lung function, and increased mortality in patients with bronchiectasis. To perform a randomized placebo-controlled study assessing the efficacy and safety of inhaled colistin in patients with bronchiectasis and chronic P. aeruginosa infection. Patients with bronchiectasis and chronic P. aeruginosa infection were enrolled within 21 days of completing a course of antipseudomonal antibiotics for an exacerbation. Participants were randomized to receive colistin (1 million IU; n = 73) or placebo (0.45% saline; n = 71) via the I-neb twice a day, for up to 6 months. The primary endpoint was time to exacerbation. Secondary endpoints included time to exacerbation based on adherence recorded by the I-neb, P. aeruginosa bacterial density, quality of life, and safety parameters. All analyses were on the intention-to-treat population. Median time (25% quartile) to exacerbation was 165 (42) versus 111 (52) days in the colistin and placebo groups, respectively (P = 0.11). In adherent patients (adherence quartiles 2-4), the median time to exacerbation was 168 (65) versus 103 (37) days in the colistin and placebo groups, respectively (P = 0.038). P. aeruginosa density was reduced after 4 (P = 0.001) and 12 weeks (P = 0.008) and the St. George's Respiratory Questionnaire total score was improved after 26 weeks (P = 0.006) in the colistin versus placebo patients, respectively. There were no safety concerns. Although the primary endpoint was not reached, this study shows that inhaled colistin is a safe and effective treatment in adherent patients with bronchiectasis and chronic P. aeruginosa infection. Clinical trial registered with http://www.isrctn.org/ (ISRCTN49790596).

Influencing factors of successful eradication of multidrug-resistant Acinetobacter baumannii in the respiratory tract with aerosolized colistin.

The increased prevalence of multidrug-resistant Acinetobacter baumannii (MDRAB) poses a worldwide treatment challenge. Although aerosolized colistin therapy for MDRAB pneumonia has attracted increasing interest, factors influencing successful eradication remain unclear. This retrospective study evaluated 135 consecutively admitted adult patients showing positive respiratory secretion cultures for MDRAB who underwent aerosolized colistin therapy between January 2007 and November 2011. Possible factors related to pneumonia and MDRAB eradication were collected for analysis. Patients with successful MDRAB eradication on Day 14 had a shorter interval between the day the positive MDRAB sputum cultures were yielded and the day colistin inhalation treatment began (4.0 ± 2.5 vs. 7.3 ± 6.5; p = 0.002). Patients with a worsening chest X-ray on Day 7 of the colistin inhalation had a lower chance of 14-day MDRAB eradication [1/44 (2.3%) vs. 8/37 (21.6%); p = 0.006]. Patients with diabetes mellitus also had a lower chance of early MDRAB eradication [13/44 (29.5%) vs. 20/37 (54.1%); p = 0.025]. Early intervention using aerosolized colistin in patients with MDRAB pneumonia or colonization can achieve better eradication.

Pharmacokinetics of colistin in critically ill patients with multidrug-resistant Gram-negative bacilli infection

Colistin, which had not been used widely because of nephrotoxicity and neurotoxicity, has gained clinical importance in recent times due to the resurgence of multidrug-resistant Gram-negative bacilli. Very few studies, especially pharmacokinetic studies, have been performed with intravenous colistimethate sodium, and none in India. The aim of our study was to study the single-dose and steady-state pharmacokinetics of colistin in patients with multidrug-resistant Gram-negative bacilli infections. This was a prospective open-label pharmacokinetic study done in an intensive care unit in a tertiary care hospital on 15 critically ill patients with proven multidrug-resistant Gram-negative bacilli infection. Colistimethate sodium was injected as intermittent intravenous infusions in accordance with the recommendations on the package insert. For patients weighing ≥ 60 kg with a normal renal function or with a creatinine clearance (CL(CR)) of between 20 and 50 ml/min, the drug was administered at 2 million international units (MIU) every 8 h; for those with a CL(CR) of 10-20 ml/min, the dose was 2 MIU every 12 h. Those patients who weighed <60 kg were administered 50,000 IU/kg/day in three divided doses at 8-h intervals. Both single-dose and steady-state pharmacokinetics of colistin were determined and correlated with clinical outcomes. A wide inter-individual variation was observed in pharmacokinetic parameters. The median (range) of the maximum plasma drug concentration/minimum inhibitory concentration (C(max)/MIC) ratio for Acinetobacter spp. was 13.4 (1.3-40.3) following the administration of a single dose of colistimethate sodium and 26.3 (0.9-64.9) at steady-state. For Pseudomonas spp., these values were 3.18 (1.6-23.1) following the single dose and 3.82 (2.3-10.9) at steady-state. For those patients whose cultures grew Acinetobacter spp., an optimum value of the C(max)/MIC ratio of >8 was achieved in seven of nine patients after the single dose and in seven of eight patients at steady-state. For those patients whose cultures grew Pseudomonas spp, only one patient after the single dose and one patient at steady-state achieved a C(max)/MIC ratio of >8. A significant association was noted between dose and survival, and a trend was observed with patients weighing ≤ 60 kg (who received 50,000 IU/kg/day instead of 6 MIU/day for those >60 kg) having an increased mortality. The pharmacokinetic parameters of colistin were comparable to those reported in previous studies in critically ill patients. However, the recommended dose may be inadequate to maintain the C(max)/MIC ratio to an optimal level-at least in patients infected with Pseudomonas spp. The dose recommendation should be based only on creatinine clearance and not body weight.

Clinical and microbiological efficacy and toxicity of colistin in patients infected with multidrug-resistant gram-negative pathogens

Polymyxins have recently again become important because of multidrug-resistant (MDR) gram-negative pathogens. The aim of this study was to evaluate the clinical and microbiological efficacy and toxicity of different dosages of colistin in patients infected with MDR microorganisms that were sensitive only to colistin. The study was conducted in the 1,200-bed Ankara Numune Training and Research Hospital. Patients with normal renal function who received colistin for 48 h or more were retrospectively evaluated. Clinical response was defined as resolution of fever and clinical and laboratory findings. Microbiological response was defined as bacteriological eradication from the infection site. Nephrotoxicity was defined as at least two consecutive serum creatinine measurements with an increase of 0.5 mg/dl from baseline at least 24 h apart after 2 or more days of colistin therapy. Twenty-four patients were included in the study: total clinical response was obtained in 17 of 24 (70.8 %) patients and microbiological response in 15 of 24 (62.5 %) patients. Patients were grouped according to colistin dosage of 3 × 1 million units (MU) versus 3 × 2 MU. Clinical response rates were 69.2 % and 72.7 %, respectively (p = 0.65). Microbiological response rate was similar (p = 0.62). Nephrotoxicity was revealed in 1 of 13 patients (7.7 %) for the 3 × 1 MU group and 2 of 11 patients (18.2 %) in the 3 × 2 MU group (p = 0.57). The nephrotoxicity rate was greater with higher dosages of colistin, but the difference was not statistically significant. Renal function of patients receiving higher dosages of colistin should be more closely monitored.

Nebulized colistin treatment of multi-resistant Acinetobacter baumannii pulmonary infection in critical ill patients

ObjectiveTo analyze the efficacy of nebulized colistin in the microbiological eradication and clinical improvement of patients with pulmonary infection by multi-resistant Acinetobacter baumannii (MAB). DesignA retrospective study. SettingIntensive Care Unit of a Tertiary hospital. PatientsHospitalized patients on invasive mechanical ventilation with positive MAB cultures of the airway. InterventionsAll received treatment with colistin (CL). Nosocomial pneumonia (NP) or Tracheobronchitis (TB) was determined according to routine criteria and colonization (CO) was determined in the case of a positive culture in the absence of infection criteria. Three groups of patients were defined: those treated with nebulized CL, those treated with IV CL and those treated with IV CL plus nebulized CL. Main measurementsBaseline characteristics. Microbiological eradication and clinical recovery were evaluated according to routine criteria. Results83 patients were studied, 54 of whom were treated, with the following diagnoses: 15 (27.8%) with NP, 16 (29.6%) with TB and 23 patients (42.6%) with CO. Nebulized CL was used in 36 patients (66.7%): 66.7% of which for CO, 33.3% in treatment for TB and in no case of NP. In 61.1% of the patients, IV CL was used: 22.2% of which for CO, 38.9% for TB and 38.9% in NP. The combination of IV CL and nebulized CL was used in 15 patients (27.8%): 5 patients (33.3%) CO, 2 patients (13.3%) TB and 8 patients (53.3%) NP. Microbiological eradication was achieved in 32 patients (59.3%), with the following distribution: 8 (47.1%) with IV CL, 15 (83.3%) with nebulized CL and 9 patients (69.2%) with a combination of IV CL and nebulized CL. Clinical recovery was achieved in 42 patients (77.8%): 12 (80%) with IV CL, 18 (94.7%) with nebulized CL and 12 (85.7%) with a combination of nebulized and IV CL. These differences were not significant. In the group of patients with infection due to TB and NP (31 patients, 57.4%), microbiological eradication was achieved in 5 patients (100%) treated with nebulized CL and in 6 of the 9 patients (42.9%) treated with IV CL, the difference being significant (P<.05). Clinical recovery in this group was 100% (6 patients) treated with nebulized CL and 75% (9 of the 12 patients) in the IV CL group. This difference was not significant. ConclusionsOur study suggests that treatment with colistin in patients with pulmonary infection with multi-resistant Acinetobacter baumannii could be more efficient if it were to be administrated solely nebulized or in combination with IV colistin rather than administered solely intravenously.

Pharmacokinetics of Colistin in an Adolescent Boy With Extensive Burn Injury

Multidrug resistance in Gram-negative bacteria has led to a resurgence in colistin use. No pharmacokinetic data exist for burn patients. A 17-year-old boy suffered a 71% TBSA full-thickness burn with deep necrosis and compartment syndrome. He developed multidrug-resistant Acinetobacter baumannii burn wound sepsis/septic shock with acute renal failure requiring dialysis. The organism was resistant to all tested antibiotics except colistin. He received colistin 2.5 mg/kg every 24 hours. Peak and trough serum concentrations, area under the concentration-time curve, and elimination half-lives of colistin were 3.6 ± 1.0 μg/ml, 0.9 ± 0.5 μg/ml, 47.1 ± 14.4 mg · hr/L, and 12.3 ± 9.4 hours (mean ± SD), respectively. Serum levels were at or above the minimum inhibitory concentration for >90% of therapy. Nevertheless, salvage therapy with colistin proved futile as the patient developed acidosis, coagulopathy, and was vasopressor-dependent without any wound healing. He died on hospital day 52. Microbiologically, the serum levels of colistin were seemingly adequate, as repeat cultures were negative. Given the peak and trough levels of colistin relative to the minimum inhibitory concentration for the organism (0.5 μg/ml), it would seem that the dosage of 2.5 mg/kg administered every 24 hours for this patient on dialysis was appropriate. Patients on dialysis infected with an organism possessing a higher inhibitory concentration (≥1 μg/ml) should probably receive the same dosage every 12 hours to avoid subtherapeutic concentrations. Large-scale study of the pharmacokinetics of colistin in patients with burn injury is urgently needed.

Prevalence and mechanism of adverse reactions to colistin in patients with cystic fibrosis

Prevalence and mechanism of adverse reactions to colistin in patients with cystic fibrosis

A Trial of Aerosolized Colistin for the Treatment of Nosocomial Pneumonia due to Multidrug-resistant Acinetobacter baumannii

Background: Recently, multidrug-resistant (MDR) A. baumannii has been implicated for a significant proportion of nosocominal pneumonia in many intensive care units (ICUs), and its acquisition may increase mortality and the length of stay in the ICU. Aerosolized colistin has been successfully used in patients with cystic fibrosis, but there is a lack of data regarding the use of aerosolized colistin in patients with nosocomial pneumonia. Methods: We conducted the present study to assess the effectiveness of aerosolized colistin for the treatment of MDR A. baumannii nosocomial pneumonia. We retrospectively reviewed the medical records of 10 patients who had been hospitalized in the medical ICU and had received aerosolized colistin as a therapy for MDR A. baumannii pneumonia. Results: The mean duration of aerosolized colistin therapy was days. Nine (90%) of 10 patients showed a favorable response to the therapy. Follow-up cultures were available for all patients, and the responsible pathogen was completely eradicated. One patient suffered from bronchospasm, which resolved after treatment with nebulized salbutamol. Conclusion: Our results corroborate previous reports that aerosolized colistin may be an effective and safe choice for the treatment of nosocomial pneumonia caused by MDR A. baumannii. Larger prospective controlled clinical studies are warranted to validate further the effectiveness and safety of aerosolized colistin therapy.

Efficacy and Safety of Colistin for the Treatment of Infections Caused by Multidrug-Resistant Isolates of Pseudomonas Aeruginosa Sensitive to Colistin in Patients with Haematological Malignancy; a Matched-Pair Analysis.

Infections due to multidrug-resistant (MDR) Gram-negative bacteria have been increasing and they are an important cause of nosocomial morbidity and mortality, especially in immunocompromised patients. In order to determine efficacy and safety of colistin (colistimethate sodium) use in the treatment of MDR Pseudomonas aeruginosa sensitive to colistin, a comparison of renal function, other toxicities, and outcome of therapy was done between a group of patients treated with colistin and patients treated with other antipseudomonas drugs as control group. A group of 26 patients that was hospitalized in our institution between February 2002 and December 2006 and treated with intravenous colistin for an infection caused by MDR P.aeruginosa was compared in a matched-pair analysis to a group of 26 patients treated with other antipseudomonas drugs. Patients were 52% male and 48% female; mean age was 37 years (range 17–63). All of the patients were treated for haematological malignancy, most received intensive chemotherapy regimens (44%), 19% received allogeneic and 31% autologous transplants. Groups of patients did not differ in age, sex, disease, or kind of treatment received. All of the patients in both groups had clinical signs of sepsis; in 69% of patients from colistin group and 84% from control group P.aeruginosa was isolated from blood, and in 27% and 12% it was isolated from skin lesions that had clinical presentation of echtyma gangrenosum, respectively. Patients treated with colistin received 3 MU of colistin every 8 hours for a mean (± SD) duration of 12.5 (± 5.4) days. Due to nature of their disease, and severity of infections, all of the patients received more than two other possibly nephrotoxic drugs; in colistin group 4 other concomitant drugs, on control group 3; most frequently vancomycin, cefepime, amikacine, garamycine and amphotericine B deoxycholate was used. Of 26 patients receiving colistin, 76.9% of patients had the drug discontinued after successful clearance of infection, while in control group 65.4% of patients had the drug discontinued due to same reason. Only one patient had displayed neurological toxicity (Jacksons attack with secondary generalisation), but the drug was not discontinued, dose was modified, patient had no further attacks. There was no statistically significant difference in the level of serum creatinine, creatinine clearance (calculated), or potassium levels between prior to therapy and after treatment discontinuation between groups. One patient treated with colistin developed renal failure and was subjected to continuous venovenous hemodiafiltration; of note is that at the time colistin introduction patient already had impaired renal function. In one patient drug was discontinued due to suspected allergic reaction. No other adverse events of colistin therapy were noted. Colistin is an effective antimicrobial drug for the treatment of severe infections caused by MDR P.aeruginosa in haematological patients. The safety profile observed is acceptable in these severe life-threatening infections, in matched-pair analysis it did not display greater toxicity than other antipseudomonas drugs. Further studies are needed to better address the treatment of MDR P. aeruginosa, naimely the optimal dose and schedule, also route of administration of colistin, as well as drug-to-drug interactions.

P099 Efficacy and safety of colistin for the treatment of infections caused by multidrug-resistant isolates of Pseudomonas aeruginosa sensitive to colistin in patients with haematological malignancy

P099 Efficacy and safety of colistin for the treatment of infections caused by multidrug-resistant isolates of Pseudomonas aeruginosa sensitive to colistin in patients with haematological malignancy

Open follow-up study of tobramycin nebuliser solution and colistin in patients with cystic fibrosis

A previous study of tobramycin nebuliser solution (TNS) compared with colistin [C] in cystic fibrosis (CF) patients, chronically infected with pseudomonas, showed benefit for the TNS treated patients over one treatment cycle only. The current report is of an extension of that study. An open randomised cross-over study of TNS compared with C was conducted on 21 patients who had previously been on the 1 cycle study. They continued for a further 5 months and then crossed over to the alternate treatment. There was an advantage for TNS over C in FEV 1 % predicted change over time. The C slope was − 0.88% per month and the TNS slope 0.35% per month ( p = 0.0002). This suggests advantages of TNS over C in a study with a small number of patients. Larger studies are required.

Pharmacokinetics of inhaled colistin in patients with cystic fibrosis: authors' response

Sir, We thank Li and Nation for their thoughtful comments on our study on pharmacokinetics of inhaled colistin in cystic fibrosis (CF) patients. It is well taken that colistin contains a varying mixture of ingredients including polymyxin E1, E2 and E3. We are not aware of any data that polymyxin E2 and E3 have antimicrobial activity, but their pharmacokinetic profile may differ from that of polymyxin E1. As our interest was focused on the antimicrobial activity of colistin, we have used the term colistin and colistin methanesulphonate interchangeably. We agree with Li and Nation that using the term colistin methanesulphonate may be the more appropriate terminology. However, since the other components of colistin have no established antimicrobial effect, this bears no direct practical relevance for treatment with inhaled colistin in CF patients where the antimicrobial activity is of primary relevance. The comment that polymyxin E1 and E2 contents may vary between different charges of the drug is well taken and also applies for the product used in this study. For treatment of the patients a batch with a known polymyxin composition containing 73% polymyxin E1 was used. Taking this composition into account the concentration of ‘total’ colistin was estimated. It is agreed that the precision of these calculations is limited due to the fact that during formation of colistin from colistin methanesulphonate a variety of different intermediates appear. At the time of sampling the composition thereof is not known. For the calibration curves of the HPLC assay Colistin sulphate European Pharmacopoeia standard (Colistin sulfate CRS batch2) was used. A molecular weight correction was performed to calculate the polymyxin E1 concentration. It is agreed that, for the sake of clarity, the clearance should be addressed as relative clearance. The term ‘apparent’ clearance was not used to prevent confusion with the term apparent volume of distribution.

Comment on: Pharmacokinetics of inhaled colistin in patients with cystic fibrosis

Sir, Ratjen et al. recently published an important paper in JAC reporting the pharmacokinetics of colistin after inhalation of colistin methanesulphonate in patients with cystic fibrosis (CF). HPLC was used to measure the concentrations of the formed colistin. The paper raises a number of important issues that deserve comment. It is important not to use the terms colistin and colistin methanesulphonate (sodium salt, or colistimethate-Na in the paper) interchangeably. The chemistry, pharmacokinetics, pharmacodynamics and toxicity of these two entities are substantially different; most importantly, colistin is formed from colistin methanesulphonate both in vitro and in vivo. Even though some manufacturers (such as Grunenthal, Germany) label the content of injection vials of colistin methanesulphonate with ‘158 mg colistin methanesulphonate is equal to 66 mg colistin’, this labelling is misleading because it is based on antibacterial activity measured with microbiological assays and does not mean that there is 66 mg of colistin in each vial. Therefore, we strongly recommend that any pharmacokinetic calculations on colistin or colistin methanesulphonate should not be based on ‘66 mg colistin’. The HPLC assay used by Ratjen et al. was very similar to the one reported previously from another laboratory using derivatization with 9-fluorenylmethyl chloroformate on solid-phase extraction C18 cartridges; in the previously reported HPLC assay, colistin sulphate was employed to prepare calibration curves for measurement of colistin (base) in biological fluids. In the paper of Ratjen et al., it is not clear whether colistin sulphate, colistin A or colistin methanesulphonate (sodium) was used for the calibration curves of the HPLC assay. Ratjen et al. reported the amount (0.18–16.13 mg) of ‘colistin methate’ recovered in urine was equal to a mean 4.3 – 1.3% (range 0.3–24.2%) of the inhaled dose. Unfortunately, it is not clear how the concentrations of ‘colistin methate’ in urine were measured. It appears that the urinary recovery was calculated based on the recovered amount of colistin (base) and the dose of ‘66 mg colistin’. Considering the hydrolysis of colistin methanesulphonate to colistin in vivo and in vitro, such calculation of urinary recovery using the dose of ‘66 mg colistin’ is inappropriate. In addition, it is unclear whether the authors have allowed for the molecular weight difference between colistin methanesulphonate (sodium, average molecular weight 1743), colistin sulphate (average molecular weight 1403, if they used it for calibration curves for colistin) and colistin (average molecular weight 1163) when the concentrations of ‘colistin’ were calculated. Ratjen et al. used the HPLC peak for polymyxin E1 to generate calibration curves for colistin concentrations. Usually, the two major components of colistin, colistin A (polymyxin E1) and colistin B (polymyxin E2), account for more than 85% of colistin, but the ratio of these two components may vary substantially between 3:1 and 1:1. It is not clear how the authors calculated the concentrations of polymyxin E1 in the HPLC assay as the commercially available colistin sulphate is a mixture of many components. In addition, we are not aware of any literature indicating that polymyxin E2 has no antibacterial activity; hence, the claim by Ratjen et al. that ‘colistin is a pro-drug that is converted into its active component polymyxin E1’ is questionable. Indeed, polymyxin E1 is one of the constituents of colistin. It should be noted that the clearance of colistin reported by Ratjen et al. should be regarded as an apparent clearance because the amount of the inhaled dose of colistin methanesulphonate reaching the systemic circulation in the form of colistin is unknown. In summary, Ratjen et al. provided some potentially useful information on the pharmacokinetics of colistin after inhalation of colistin methanesulphonate. However, because of lack of clarity regarding the quantification of colistin in biological fluids and the pharmacokinetic analysis, caution is required when these data are used as reference for inhalation therapy of colistin methanesulphonate in CF patients.

Pharmacokinetics of inhaled colistin in patients with cystic fibrosis

Inhaled colistin is commonly used in patients with cystic fibrosis (CF), but only limited data are available to define its pharmacokinetic profile. We performed a multicentre study in 30 CF patients to assess sputum, serum and urine concentrations after a single dose of 2 million units of colistin administered by inhalation. In a subgroup of patients we also compared the efficacy of two different nebulizers for administration of inhaled colistin. Serum concentrations of colistin reached their maximum 1.5 h after inhalation and decreased thereafter. Serum concentrations were well below those previously reported for systemic application in all patients. A mean 4.3+/-1.3% of the inhaled dose was detected in urine. Elimination characteristics did not differ significantly from those previously reported for systemic application. A positive correlation was found between forced expiratory volume in 1 s (FEV1) in per cent predicted and both AUC and maximal colistin concentrations in serum (Cmax). Maximum sputum concentrations were at least 10 times higher than the MIC breakpoint for Pseudomonas aeruginosa proposed by the British Society for Antimicrobial Chemotherapy. Although sputum drug concentrations decreased after a peak at 1 h, the mean colistin concentrations were still above 4 mg/L after 12 h. No differences were seen in polymyxin E sputum concentrations, for CF patients between the two nebulizer systems. The low systemic and high local concentrations of colistin support the use of inhaled colistin in CF patients infected with P. aeruginosa.

Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis

IntroductionThe clinical and economic consequences of the emergence of multidrug-resistant Gram-negative bacteria in the intensive care unit (ICU) setting, combined with the high mortality rate among patients with nosocomial pneumonia, have stimulated a search for alternative therapeutic options to treat such infections. The use of adjunctive therapy with aerosolized colistin represents one of these. There is extensive experience with use of aerosolized colistin by patients with cystic fibrosis, but there is a lack of data regarding the use of aerosolized colistin in patients without cystic fibrosis.MethodsWe conducted the present study to assess the safety and effectiveness of aerosolized colistin as an adjunct to intravenous antimicrobial therapy for treatment of Gram-negative nosocomial pneumonia. We retrospectively reviewed the medical records of patients hospitalized in a 450-bed tertiary care hospital during the period from October 2000 to January 2004, and who received aerosolized colistin as adjunctive therapy for multidrug-resistant pneumonia.ResultsEight patients received aerosolized colistin. All patients had been admitted to the ICU, with mean Acute Physiological and Chronic Health Evaluation II scores on the day of ICU admission and on day 1 of aerosolized colistin administration of 14.6 and 17.1, respectively. Six of the eight patients had ventilator-associated pneumonia. The responsible pathogens were Acinetobacter baumannii (in seven out of eight cases) and Pseudomonas aeruginosa (in one out of eight cases) strains. Half of the isolated pathogens were sensitive only to colistin. The daily dose of aerosolized colistin ranged from 1.5 to 6 million IU (divided into three or four doses), and the mean duration of administration was 10.5 days. Seven out of eight patients received concomitant intravenous treatment with colistin or other antimicrobial agents. The pneumonia was observed to respond to treatment in seven out of eight patients (four were cured and three improved [they were transferred to another facility]). One patient deteriorated and died from septic shock and multiple organ failure. Aerosolized colistin was well tolerated by all patients; no bronchoconstriction or chest tightness was reported.ConclusionAerosolized colistin may be a beneficial adjunctive treatment in the management of nosocomial pneumonia (ventilator associated or not) due to multidrug-resistant Gram-negative bacteria.

Steady-state pharmacokinetics of intravenous colistin methanesulphonate in patients with cystic fibrosis.

To define the steady-state pharmacokinetics of colistin methanesulphonate and colistin in patients with cystic fibrosis (CF) following intravenous administration of the former. The study was conducted in 12 patients with CF following intravenous administration of colistin methanesulphonate (1.63-3.11 mg/kg) every 8 h for at least 2 days. On the day of study, four blood samples were collected from each patient at 60, 120, 240 and 360 min after the end of the infusion. Concentrations of colistin methanesulphonate and colistin in plasma were measured separately by HPLC. At steady-state, colistin methanesulphonate had a mean (+/- S.D.) total body clearance, volume of distribution and half-life of 2.01 +/- 0.46 mL/min per kg, 340 +/- 95 mL/kg and 124 +/- 52 min, respectively. Colistin had a significantly longer mean half-life of 251 +/- 79 min (P<0.001). With the regimen used, colistin methanesulphonate was well tolerated. This is the first report on the pharmacokinetics of colistin methanesulphonate in CF patients determined using concentrations of colistin methanesulphonate and colistin in plasma. Based on the in vitro pharmacodynamics against Pseudomonas aeruginosa previously published by our group and these pharmacokinetic findings, dose escalating trials may be warranted to maximize efficacy.