Colistin

Study objectives: To develop practical ways of nebulizing colistin by determining the rate of drug output, total drug output, and particle-size distribution of two commercially available jet nebulizers, the disposable Hudson 1730 Updraft II (Hudson Respiratory Care; Temecula, CA) and the reusable Pari LC Star breath-enhanced nebulizer (Pari Respiratory Equipment; Midlothian, VA).

Methods: The nebulizers contained colistin, 75 mg, in 4 mL of isotonic solution. Particle-size distribution was measured by helium-neon laser diffraction, allowing calculation of the respirable fraction (RF), the mass of aerosol comprised of droplets [is less than] 5 [micro]m.

Results: The mean (95% confidence interval [CI]) total rate of output of the Updraft II was 2.6 mg/min (2.0, 3.1; n = 4) with 1.3 mg/min (1.0, 1.5) mg/min within the RF. The rate of output of the LC Star increased in a quadratic relationship to the inspiratory flow, delivering 1.8 mg/min (0.7, 2.0; n = 4) with 1.4 mg/min (1.3, 1.6) within the RF, and 6.2 mg/min (5.6, 6.8) with 5.3 mg/min (4.8, 5.7) within the RF, at 0 L/min and 20 L/min inspiratory flows, respectively. Efficiency, as the rate of expected pulmonary deposition divided by rate of total output, was then calculated. The LC Star estimated 56% (51, 61) efficiency, with pulmonary delivery of 29% (26, 32) of the charge of the nebulizer, compared to the Updraft II at 22% (22, 23) efficiency and expected pulmonary deposition of 10% (10, 10) of the dose.

Conclusions: Colistin can be successfully nebulized with both nebulizers tested. This study provides an estimate of in vivo efficiency and expected pulmonary deposition that may be used in future trials.

(CHEST 2001; 119:250-255)

Key words: cystic fibrosis; inhaled antibiotics; nebulizing colistin; Pseudomonas aeruginosa

Abbreviations: CF = cystic fibrosis; CI = confidence interval; MMD = mass median diameter; RF = respirable fraction; TE = expiratory time; TI = inspiratory time; VR = residual volume of liquid remaining in nebulizer

The use of aerosolized antibiotics has contributed to an improved quality of life for patients with cystic fibrosis (CF) by decreasing relapses of chest infections and, thereby, hospital admissions.[1,2] Increasing patterns of resistance to both tobramycin and gentamicin aerosols, however, prompt the ongoing search for other inhaled antibiotics. Colistin, a polymyxin, has been shown in vitro to be active against most strains of Pseudomonas aeruginosa, even those deemed to be multidrug-resistant to other antibiotics.[3] Its use parenterally has been limited by systemic toxicity,[4] giving rise to increasing interest in administering the agent by inhalation. One study of 20 CF patients with multidrug-resistant P aeruginosa awaiting lung transplantation demonstrated a return to conventional antibiotic sensitivities following inhalation of colistin in all patients, as compared to an untreated control group, in which only 30% of patients developed sensitive isolates.[5] European studies have suggested the efficacy of nebulized colistin in maintenance of pulmonary function and in decreasing the frequency and number of pseudomonas organisms isolated from respiratory tract cultures. One study suggested inhaled colistin could delay chronic colonization (or infection) in CF patients with pseudomonas, compared to a historical control group.[6] A small, prospective, double-blind, placebo-controlled study of colistin inhalation, carried out on 40 CF patients with chronic bronchopulmonary P aeruginosa infection, found that colistin treatment was superior to placebo, demonstrated by a significantly better clinical symptom score.[4] Prospective, double-blind, randomized, controlled trials to determine whether colistin treatment is effective for CF patients with multidrug-resistant pseudomonal organisms, or more effective than tobramycin for nonresistant organisms, have yet to be done.

Delivery of nebulized colistin is complicated by foaming in aerosol devices.[7,8] This may alter the functional geometry of the baffle system within the nebulizer and could affect particle size distribution. Some centers therefore add a small amount of ethanol to increase surface tension and reduce foaming. To date, however, the in vitro performance of jet nebulizers aerosolizing colistin has not been described. Hence, characterization of the behavior of colistin in a nebulizer must first be undertaken in order to choose the most appropriate delivery system for colistin and to estimate its deposition in the lung. The aims of this study were to develop practical ways of nebulizing colistin by determining the rate of drug output of two commercially available jet nebulizers of good quality, one disposable for in-patient use, the other reusable for home use.

MATERIALS AND METHODS

Two nebulizers were chosen for the study: the disposable unvented Hudson 1730 Updraft II (Hudson Respiratory Care; Temecula, CA) and the breath-enhanced Pari LC Star (Pari Respiratory Equipment; Midlothian, VA). The Updraft II has proven efficacious in a previous trial of aerosolized tobramycin[9] and favorable to other devices of its type.[10] The Pari LC Star has a smaller particle-size distribution,[11] and hence should be more efficient than the Pari LC Jet (Pari Respiratory Equipment), which has already proven superior in in vitro trials, in terms of a higher respirable fraction (RF) and less drug wastage compared to unvented nebulizers.[12] The Pari LC Star has also proven to be superior to the other breath-enhanced nebulizers available in North America.[13] The Pari ProNeb Turbo compressor (Pari Respiratory Equipment) was used to drive the LC Star at 4.5 L/min, and the Updraft II was driven by a dry gas source at 6 L/min, analogous to use in the hospital environment. The flow through both types of nebulizers was confirmed by the use of a flow-calibration instrument (Timeter RT 200; Allied Health Care Products; St. Louis, MO). Four nebulizers of each type were subsequently used. Total nebulizer output and output within the RF were evaluated in order to determine nebulizer efficacy and drug wastage. The effect of adding ethanol as an antifoaming agent was also considered.

The dose of colistin, 75 mg, was nebulized both with and without the addition of 100% ethanol. The ethanol was added in increasing volumes of 200 to 800 [micro]L, to four nebulizers of each type, to determine its effect on decreasing foaming within the nebulizer and increasing drug output. This dose (with or without ethanol) was then diluted with isotonic saline solution to a total fill volume of 4 mL.

Each nebulizer was weighed dry, after filling and at end-nebulization to allow calculation of the residual volume of liquid remaining in the nebulizer (Va). Prior to initial and following postnebulization weighing, a 10-[micro]L sample was obtained and assayed for osmolality by vapor pressure osmometry (Wescor Vapor Pressure Osmometer 5500; Logan, UT).[14]

Nebulizers were clamped vertically with a T piece and mouth-piece attached so that the aerosol released passed through the helium-neon laser beam of the particle sizer (Malvern Mastersizer X; Malvern Instruments; Worcestershire, UK) 24 mm from the lens.[15] The center of the mouthpiece was placed 2 cm from the center of the laser beam and was varied from a horizontal to a vertical position to optimize the obscuration factor (10 to 30%) of the beam. The Malvern presentation 2QAA was selected, based on the Mie theory for transparent spheres. Aerosol was prevented from refluxing onto the lens by venting it away through a funnel attached to a partial vacuum. Particle size was measured after 2 min of nebulization in order to achieve thermal stability.[16] It was expressed as mass median diameter (MMD) with 95% confidence intervals (CIs). From this, the RF,[12] defined as the fraction of the aerosol mass comprised of particles [is less than] 5 [micro]m,[17] was calculated and served as one of the primary outcome measures.

In addition to particle-size distribution, measurements consisted of rate of output and total output for each device. As these parameters are affected by inspiratory flow through a breath-enhanced nebulizer, "inspired" air flow through the LC Star was mimicked by introducing air with controlled 40 to 45% relative humidity into the top of the nebulizer at 0, 10, and 20 L/min.[12] Since the unvented device is unaffected by respiratory activity,[12] these measurements were made under ambient conditions of temperature and humidity for the Updraft II.

Total drug output was determined by runs until nebulization was completed. End-nebulization was defined as the time at which no visible mist was seen passing the laser beam for 10 s,[17,18] although nebulizer output might have become intermittent before that time. Based on preliminary studies showing that after approximately 85% of total drug output had occurred, osmolality increased above 500 mmol/L; end points were redefined to prevent the inhalation of a hyperosmolar solution, which has been associated with cough.[19] Furthermore, output of the device to "end-nebulization"[17] after 85% of the drug had been nebulized was erratic and so slow that patients would not be expected to use the device to dryness. Hence, the "total output" for the purpose of this study was measured at the point when 85% of the colistin was nebulized. For the LC Star, these points were at 25, 15, and 8 min for 0, 10, and 20 L/min of inspiratory flows through the nebulizer, respectively. Rate of drug output was determined by timed runs to approximately two thirds of the 85% point, to ensure that no tailing off of the output occurred toward the end of nebulization. These times were 12, 5, and 4 min for 0, 10, and 20 L/min of inspiratory flows, respectively. Total output runs for the Updraft II were 15 min long, with timed runs ending at 5 min.

Nebulizer output was calculated as the initial mass of colistin solution, minus the VR times the final concentration of the solution. This took into account the concentrating effect of the nebulizer through drying.[20] Ultraviolet spectrophotometry could not be used to verify drug concentration, as colistin does not contain a chromophore, which is necessary to use this method of analysis. There is an excellent agreement, however, with changes in osmolality and chemical analysis for other antibiotics.[14]

Output = 75 mg - ([VR x initial concentration]

x [final osmolality/initial osmolality])[12,14,17]

where initial concentration = 75 mg colistin/4 mL solution = 18.75 mg/mL; final osmolality = osmolality of remaining solution at end-nebulization; and initial osmolality = osmolality of solution prior to nebulization.

For both types of devices, the duration of inspiratory time (TI) in relation to expiratory time (TE) contributes to the operating efficiency since nebulized drug is wasted during expiration. Inspiratory flow is also a factor when using breath-enhanced devices, since the rate of output increases with increasing flow.[12] The efficiency of colistin deposition via each type of device was then estimated based on data from three "typical" CF patients of different sizes and degrees of disease, generated from their respiratory parameters while breathing through nebulizers (Table 1).[21]

[TABULAR DATA 1 NOT REPRODUCIBLE IN ASCII]

For the LC Star breath-enhanced nebulizer, percent efficiency is dependent on the entrained flow through the nebulizer. It was therefore defined as the output within the RF during inspiration divided by the total output during a full respiratory cycle.[21]

% Efficiency (Pari LC Star) = Rate ORF at entrained flow x TI/ (Rate OTOT at entrained flow x TI) + (Rate OTOT at no entrained flow x TE)

where Rate ORF = rate of drug output in RF (milligrams per minute); Rate OTOT = rate of total drug output (milligrams per minute); and entrained flow = patient's mean inspiratory flow (tidal volume/TI) - nebulizing flow (4.5 L/min).

The relationship between inspiratory flow (liters per minute) and the rate of output of the LC Star nebulizer was determined by fitting a quadratic equation to the data points.[12] This allowed the selection of the rate specific for the amount of flow that the patient would have entrained.

For the Updraft II nebulizer, inspiratory flow is not entrained into the nebulizer and does not affect nebulizer output, thereby simplifying the equation.

% Efficiency (Hudson 1730 Updraft II) = Rate ORF x TI/Rate OTOT x TTOT

where Rate ORF = rate of drug output in RF (liters per minute); Rate OTOT = rate of total drug output (liters per minute); and TTOT = total time (in seconds) for one respiration.

Estimated pulmonary deposition of colistin could then be determined from the product of device efficiency and total drug output from the nebulizer at the end point (85% maximal nebulizer output).

Estimated drug deposition in lung (milligrams) = % Efficiency

x 85% total drug output (milligrams)

The percent of the initial 75-mg drug dose expected to be delivered to a patient could finally be calculated by dividing the drug deposited in the lung by the initial 75-mg charge. This constituted the estimated efficacy of the nebulizer in delivering drug to a patient.

RESULTS

While direct observation revealed that foaming in the nebulizer decreased with the addition of ethanol, no significant difference was noted for either the Updraft II or the LC Star, in terms of MMD, total drug output, RF, or rates of drug output, as compared to when no ethanol was added (Table 2). Hence, it was decided, based on the potential toxicity or adverse microbiological effects for minimal benefit, that the use of ethanol in the remainder of our study was not warranted.

[TABULAR DATA 2 NOT REPRODUCIBLE IN ASCII]

The total output of the Updraft II nebulizer was approximately half of the initial charge of solution, of which more than half was within the RF. The total output of the LC Star was greater than that of the Updraft II, with almost 80% in the RF. The mean (95% CI) total rate of output for the Updraft II was 2.5 mg/min (2.0, 3.1; n = 4), with 1.3 mg/min (1.0, 1.5) within the RF. The rate of output of the LC Star was 1.8 mg/min (1.5, 2.0), of which 1.4 mg/min (1.3, 1.6) was within the RF (Table 3) Furthermore, for the LC Star nebulizer, total rate of output increased in a quadratic relationship to the amount of inspiratory flow (Fig 1), with the RF remaining constant.

[Figure 1 ILLUSTRATION OMITTED]

[TABULAR DATA 3 NOT REPRODUCIBLE IN ASCII]

Using pattern of breathing data from three patients with CF, the mean estimated efficiency of the LC Star was 56% (51, 61; n = 4), giving an expected delivery of 21.5 mg (19.5, 23.5), or 29% (26, 32) of the initial 75-mg dose of colistin, at end-nebulization. The Updraft II, in contrast, was only 22% (22, 23) efficient, providing 7.7 mg (7.5, 8.0) of colistin within the RF, on average, or 10% (10, 10) of the initial dose (Table 4).

[TABULAR DATA 4 NOT REPRODUCIBLE IN ASCII]

DISCUSSION

This study demonstrates that colistin could be successfully nebulized with both a disposable Up draft II for in-hospital use and by the breathenhanced LC Star for home use. While the total drug output of both nebulizers was similar, the LC Star was a more efficient vehicle for delivery of inhaled colistin due its breath-enhanced quality that delivered relatively higher rates of output during inspiration as compared to expiration, and thereby minimized drug wastage and reduced nebulization time. This was expected, given the past experience of increased drug delivery from breath-enhanced nebulizers as compared to conventional devices.[7,12] The most striking result, however, was the magnitude of difference in expected drug delivery between the two nebulizers. When the rate of output for each nebulizer was incorporated with pattern of breathing data from three patients with CF, pulmonary drug deposition was estimated to be almost three times greater for the LC Star as compared to the Updraft II.

While nebulizer type influences performance, the solution itself, particularly with regard to surface tension, also plays a role.[17] The dose and volume of solution used were chosen based on previous clinical work with colistin and other nebulized compounds. A 4-mL fill volume was chosen, based on studies showing that increasing the liquid volume from 2 to 4 mL caused an increase in drug release from 50%, to 60 to 80%.[16] The larger the volume, however, the longer the nebulization time. It was believed that a fill volume [is greater than] 4 mL would likely result in a nebulization time of sufficient duration to hinder patient compliance.

A 75-mg dose of colistin was selected for several reasons. A study of the effect of antibiotic concentration on nebulizer performance reported that concentrations of colistin [is greater than] 75 mg/mL in normal saline solution consistently produced marked foaming in all aerosol devices, precluding assessment of aerosol output.[7] Furthermore, in a study of the clinical effect of increasing tonicity of inhaled colistin solutions, it was suggested that the higher the tonicity, the greater the symptoms of chest tightness experienced by recipients.[22] Hence, the concern about inducing bronchospasm by administering a hypertonic solution to patients forced the redefinition of the point of end-nebulization,[19,23-25] which was chosen as the time at which osmolality increased to [is greater than] 500 mmol/kg, determined by timed runs. This was significantly shorter than the original end point.

There are limitations of this methodology when extrapolating conclusions directly to the expected in vivo behavior of this compound or the devices. In vitro, the nebulizer is damped vertically in position, whereas patients may tend to tip the nebulizer toward them or tap on the sides of the nebulizer, which may facilitate the passage of larger droplets or foam through the mouthpiece. While the calculation of drug output based on the initial charge minus what remains in the nebulizer at the end of the nebulization run is commonly used,[7,26,27] a recent deposition study[28] suggests that drying of droplets on the baffles and connecting tubing may result in a 10% overestimation of the true drug output. This is because the sample taken at the end of the nebulization run used to calculate drug concentration comes from the well of the nebulizer and may not reflect desiccated or highly concentrated drug in droplets on the baffles. The behavior of the LC Star nebulizing colistin differs from that of the LC Jet nebulizing tobramycin,[12] in that there was a progressive increase in rate of output over the entire range of entrained flow (Fig 1) and no change in RF. The LC Jet, when nebulizing tobramycin[12] shows a plateau in rate of output at 15 L/min of entrained flow and a progressive increase in RF. Without using an entrained flow, Barry and O'Callaghan[29] found an RF of 0.68 and an MMD of 4.0 [micro]m for the LC Star while nebulizing albuterol. Wildhaber and colleagues[11] found a virtually identical MMD using the LC Star to nebulize albuterol, as was found in this study. However, it is hard to compare total output since, in that study,[11] a fill volume of only 2 mL was used and the nebulization time, with children 6 to 8 years of age breathing on the device, was limited to 5 min. However, when recalculating the deposition data from that study, the nebulizer output rate was approximately 9% of the initial charge per minute, which would be similar to our findings for the output of colistin for entrained flows between 10 L/min and 20 L/min. What was different in that study[11] was the in vivo RF (lung deposition divided by total body deposition) of 0.46, compared to the in vitro RF of 0.82 in the present study, despite virtually identical MMDs. One explanation could be that the particle sizing that was done during steady-state thermal equilibrium conditions[30] differed from that seen with the dynamic changes during respiration. However, comparisons of in vitro vs in vivo RF in normal adults[28,31] showed excellent agreement. The explanation for the discrepancy may be that the RF is much less in small children than it is in adults. Hence, the assumption that particles of [is less than or equal to] 5 [micro]m are likely to deposit in the respiratory tract of children may need to be reassessed. In other words, the expected pulmonary deposition presented in the present study may be an overestimation, particularly for the example given for the 7-year-old child. However, since both nebulizers would be affected, the comparison between the two would not be significantly altered. It is difficult to quantify the extent of this overestimation. In a deposition study by Diot and colleagues[32] with CF subjects from 6 to 31 years old, a variety of devices, including the Pari LC Jet, were tested; deposition fractions ranged from 6 to 31% of the initial dose of recombinant human deoxyribonuclease placed in the nebulizer, values that are clearly in the same range as those estimated for colistin in the present study. In another deposition study of nebulizing colistin with the Pari LL nebulizer (Pari Respiratory Equipment), an interrupter device, Gagnadoux and colleagues[33] found deposition fractions similar to those suggested in the present study for those subjects with sufficient coordination to use the device. Furthermore, the close to three-fold difference seen in the performance between the two devices is in keeping with the data of Barry and O'Callaghan[29] who, using a filter collection study with simulated respiration, found very similar results when comparing the LC Star to the Cirrus (Intersurgical; Wokingham, UK), a nonvented nebulizer. Based on previous deposition studies with the Pari LC Jet,[31] they estimated a 21% pulmonary deposition from the Pari LC Star.[29] Given that that same study used a 2.5-mL fill volume compared to the more efficient[10] 4-mL fill volume coupled with the higher RF in the present study, the estimated pulmonary deposition data are certainly in keeping with what would be expected from the data in the literature. Finally, the estimates of deposition based on patients' respiratory patterns used in this study assumes ideal conditions where all breaths are identical. Clearly, in the real world, there are significant differences from the assumption, which would likely reduce the actual pulmonary drug deposition.

In conclusion, colistin may offer therapeutic options for patients with CF. The behavior of nebulized colistin has now been characterized, and estimates of pulmonary deposition have been made for both an unvented nebulizer and a breath-enhanced device. The Pari LC Star was estimated to deliver close to one third of the charge of the nebulizer to a patient in the RF, whereas one eighth was delivered from the Updraft II. Based on these data, dosing for the administration of inhaled colistin to patients both in hospital and at home can be estimated for future clinical trials of aerosolized colistin treatment for patients with multidrug-resistant pseudomonal organisms.

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[33] Gagnadoux F, Diot P, Marchand S, et al. Deposition pulmonaire des aerosols de colistine dans la mucoviscidose: comparaison d'un nebuliseur ultrasonique et d'un pneumatique. Rev Mal Respir 1996; 13:55-60

(*) From the Division of Respiratory Medicine, Hospital for Sick Children, University of Toronto, Toronto, Canada. Supported in part by the Canadian Cystic Fibrosis Foundation & Parke-Davis Canada, Ltd.

Please note that Parke-Davis Canada markets this inhalation agent under the proprietary name Colistin in Canada. Manuscript received April 27, 2000; revision accepted June 29, 2000.

Correspondence to: Allan Coates, MDCM, Division of Respiratory Medicine, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8; e-mail: allan.coates@ sickkids.on.ca

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