Abstract
Rationale: Lower respiratory tract infection with Pseudomonas aeruginosa (PA) is associated with increased morbidity in patients with cystic fibrosis (CF). Current treatment guidelines for inhaled antibiotics are not universally followed due to the perception of decreased efficacy, increasing resistance, drug intolerance, and high treatment burden with current aerosol antibiotics. New treatment options for CF pulmonary infections are needed.
Objectives: This study assessed the efficacy and safety of a novel aerosol formulation of levofloxacin (MP-376, Aeroquin) in a heavily treated CF population with PA infection.
Methods: This study randomized 151 patients with CF with chronic PA infection to one of three doses of MP-376 (120 mg every day, 240 mg every day, 240 mg twice a day) or placebo for 28 days. The primary efficacy endpoint was the change in sputum PA density. Secondary endpoints included changes in pulmonary function, the need for other anti-PA antimicrobials, changes in patient-reported symptom scores, and safety monitoring.
Measurements and Main Results: All doses of MP-376 resulted in reduced sputum PA density at Day 28, with MP-376 240 mg twice a day showing a 0.96 log difference compared with placebo (P = 0.001). There was a dose-dependent increase in FEV1 for MP-376, with a difference of 8.7% in FEV1 between the 240 mg twice a day group and placebo (P = 0.003). Significant reductions (61–79%) in the need for other anti-PA antimicrobials were observed with all MP-376 treatment groups compared with placebo. MP-376 was generally well tolerated relative to placebo.
Conclusions: Nebulized MP-376was well tolerated and demonstrated significant clinical efficacy in heavily treated patients with CF with PA lung infection.
Clinical trial registered with www.clinicaltrials.gov (NCT00677365).
There is a recognized need for more treatment options for patients with cystic fibrosis (CF) with Pseudomonas aeruginosa airway infections. This study examines the safety and efficacy of a novel formulation of inhaled levofloxacin (MP-376) in a population of patients with CF with a history of heavy exposure to other inhaled antibiotics and chronic airway therapies.
The results suggest significant responses to MP-376, including reduced bacterial density in sputum, the primary endpoint of the study, and the secondary endpoints of improved pulmonary function, prolonged time to need for other antibiotics, and improved patient-reported outcome scores. Therefore, MP-376 represents a potential treatment option for management of airway infections in patients with CF.
Aerosol delivery of antibiotics directly to the airways yields high concentrations at the site of infection while minimizing systemic exposure (6). Current options of aerosol antibiotics are limited. Tobramycin inhalation solution (TIS) improves pulmonary function and reduces hospital days when used as alternate-month therapy (7). Recently approved inhaled aztreonam lysinate (AZLI or Cayston; Gilead Sciences, Foster City, CA) improved patient reported outcomes and FEV1 after 28 days of treatment (8). Inhaled colistimethate is not approved in the United States but has been widely used in Europe for CF airway infections.
Despite current CF treatment guidelines for chronic PA infection (9, 10), one-third of eligible patients with CF do not use TIS (11), either because of drug intolerance, treatment burden, or the perception that it is no longer effective. In addition, adherence is low for TIS in children, as measured by a treatment diary (12), and according to claims data, a small minority of eligible patients fill at least four prescriptions per year (13). Even in more adherent patients (e.g., during clinical trials) a further decline in lung function and recurrent pulmonary exacerbations still occur with alternate-month cycling (14). Consequently, some clinicians prescribe continuous antibiotics or cycle different antibiotics every other month (15). Therefore, additional classes of inhaled antimicrobials are needed to provide treatment options for patients with CF with chronic airways infection.
Levofloxacin is a fluoroquinolone with potent activity against CF pathogens, including PA, and is not inactivated by CF sputum (16). The bacterial killing and clinical response to oral and parenteral fluoroquinolones have been established (17–19), and they are extensively used in patients with CF for airway infections.
A novel formulation of levofloxacin (MP-376, Aeroquin; Mpex Pharmaceuticals, Inc., San Diego, CA) has been developed for aerosolization to treat endobronchial infections in CF. MP-376 contains high concentrations of levofloxacin along with magnesium chloride that enables rapid administration using a customized, vibrating, perforated-membrane eFlow nebulizer (PARI Pharma, Munich, Germany). Ascending-dose studies of MP-376 in patients with CF for up to 14 days of treatment demonstrated dose-related increases of levofloxacin in serum and sputum, good safety and tolerability, and early evidence of clinical effectiveness compared with placebo (20, 21). MP-376 produced very high sputum concentrations with low serum exposure. Based on these promising initial results, a randomized, placebo-controlled study was conducted to evaluate the efficacy, safety, and tolerability of three doses of MP-376 administered for 28 days in a CF population with significant prior exposure to inhaled antibiotics as well as other chronic treatments for health maintenance in CF. The results of this study have been previously published in abstract form (22, 23).
This randomized, double-blind study was conducted at 51 CF Centers in the United States and Europe (June 2008–June 2009). The Institutional Review Board for each site approved the study and all patients or their guardians provided written informed consent.
After a 14-day screening period, eligible patients were randomly assigned (1:1:1:1) to either one of three MP-376 dosing regimens (120 mg [1.2 ml] every day, 240 mg [2.4 ml] every day, 240 mg [2.4 ml] twice a day) or a placebo group that was subdivided to match the volume and dosing frequency of one of the MP-376 regimens (Figure 1). MP-376 had a 100 mg/ml concentration of levofloxacin, and study drug was delivered with an investigational eFlow nebulizer. The first dose of MP-376 or placebo was administered at the study site to monitor for drug intolerance, defined as a decline from baseline in FEV1 of 20% or greater at 30 minutes post dose, oxygen saturation less than 90% within 30 minutes post dose, severe coughing, chest tightness, throat discomfort, or moderate to severe dyspnea. Patients self-administered study drug for the remainder of the treatment period and returned for monitoring on Days 7, 14, and 28. Patients were followed for an additional 28 days after the last dose. (Figure 1)
Figure 1. Study design and patient disposition. AE = adverse event; BID = twice a day; CF = cystic fibrosis; MITT = modified intent to treat; QD = every day.
[More] [Minimize]Inclusion criteria included diagnosis of CF, age 16 years or older, FEV1 between 25 and 85% predicted values (24), clinically stable, and a sputum specimen positive for PA at screening and within the past 18 months. Patients must have received three or more courses of inhaled antimicrobials over the preceding year, with completion of at least one course in the 30 to 56 days before Visit 1. Exclusion criteria included use of any investigational agents or antipseudomonal antibiotics, or changes in the CF medical regimen within 30 days before Visit 1. Detailed inclusion and exclusion criteria are provided in the online supplement.
Procedures performed at various study visits included interval history, physical examination, spirometry (post-bronchodilator), collection of sputum for qualitative and quantitative culture, and administration of the Cystic Fibrosis Questionnaire—Revised (CFQ-R). The primary efficacy endpoint was change in sputum PA density (colony-forming units [cfu]/g sputum, log10 transformed) from Day 1 to Day 28. Major secondary efficacy endpoints included changes in pulmonary function, time to need for other antipseudomonal antimicrobials, and changes in clinical symptoms (respiratory domain of CFQ-R) (25). Patients received additional anti-PA antimicrobials at the discretion of the primary investigator; however, use of anti-PA antimicrobials was only captured as an event in the time to anti-PA analysis if they also met one of four symptoms as defined by Rosenfeld and colleagues: increase in cough, increase in sputum production/chest congestion, decrease in exercise tolerance, or decrease in appetite (26).
Safety was assessed by monitoring adverse events, changes in clinical laboratory values, vital signs, abnormal physical examination findings, electrocardiograms, and acute change in pulmonary function after dosing.
Analyses are reported on a modified intent to treat (MITT/Safety) patient population (Figure 1), defined as any randomized patient who received a dose of study drug. Patients receiving placebo were pooled for the purpose of analysis after demonstrating that the groups were not statistically different. Comparisons between the active drug and placebo during the 28-day treatment phase used a repeated measures mixed model that included treatment group, visit, treatment by visit interaction, geographical region, baseline values, and visit by baseline interaction.
Comparisons of the time to need for other antipseudomonal antimicrobials between active drug and placebo was assessed using a Cox proportional hazards regression model. Patients who did not require antipseudomonal antimicrobials before discontinuation from the study were censored at the date of discontinuation. The proportion of patients who required antipseudomonal antimicrobials was also compared among treatment groups using Fisher exact test.
A sample size of 128 patients was estimated as providing 80% power to detect a difference between treatment arms using a two-sided analysis of variance, with α = 0.05. This estimate assumed an SD of 1.5 and a mean log cfu change in P. aeruginosa of −0.75, −0.75, no change, and 0.25 increase for the MP-376 240 mg twice a day, MP-376 240 mg every day, MP-376 120 mg every day, and placebo arms, respectively.
Of 180 patients screened, 151 patients were randomized into the study and 143 (95%) completed the study. The reasons for most of the screen failures were that subjects did not satisfy all of the inclusion and exclusion criteria, or they had a respiratory exacerbation during the screening period. Five patients (two in the placebo group and three in MP-376 groups) discontinued the study due to adverse events during the 28-day treatment period (Figure 1).
Baseline characteristics of all patients were similar in each treatment arm (Table 1). Patients were an average of 28.7 years of age and were predominantly white. At baseline, mean FEV1 percent predicted was 52.3%. The average number of inhaled antibiotic courses per patient used in the prior year was 4.8, with 59 patients (39%) having received six or more courses. Other important respiratory medications used at baseline and continued throughout the study were dornase alfa (78%), azithromycin (74%), and hypertonic saline (46%). Importantly, at baseline 62% of PA isolates were not susceptible to levofloxacin based on a minimum inhibitory concentration (MIC) greater than 2μg/ml, the breakpoint used for systemic dosing with levofloxacin.
Placebo (n = 37) | MP-376 120 mg Every Day (n = 38) | MP-376 240 mg Every Day (n = 37) | MP-376 240 mg Twice a Day (n = 39) | All Patients (N = 151) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Age, yr, mean (SD) | 30.1 (9.9) | 28.0 (6.9) | 27.5 (9.1) | 29.2 (10.0) | 28.7 (9.0) | |||||
| Male, n (%) | 19 (51.4) | 20 (52.6) | 21 (56.8) | 25 (64.1) | 85 (56.3) | |||||
| White, n (%) | 36 (97.3) | 37 (97.4) | 37 (100.0) | 39 (100.0) | 149 (98.7) | |||||
| United States, n (%) | 30 (81.1) | 32 (84.2) | 30 (81.1) | 32 (82.1) | 124 (82.1) | |||||
| FEV1, % predicted, mean (SD) | 52.4 (13.4) | 52.9 (17.7) | 55.4 (14.4) | 48.8 (15.2) | 52.3 (15.3) | |||||
| BMI, kg/m2, mean (SD) | 21.0 (3.4) | 21.2 (3.4) | 20.9 (3.3) | 21.8 (2.6) | 21.3 (3.2) | |||||
| Other respiratory medications | ||||||||||
| Dornase alfa, n (%) | 31 (83.8) | 26 (68.4) | 32 (86.5) | 29 (74.4) | 118 (78.1) | |||||
| Azithromycin, n (%) | 25 (67.6) | 29 (76.3) | 26 (70.3) | 32 (82.1) | 112 (74.2) | |||||
| Salbutamol, n (%) | 25 (67.6) | 29 (76.3) | 25 (67.6) | 23 (59.0) | 102 (67.5) | |||||
| Hypertonic saline, n (%) | 22 (59.5) | 13 (34.2) | 13 (35.1) | 22 (56.4) | 70 (46.4) | |||||
| Inhaled antibiotic courses previous 12 mo | ||||||||||
| Mean (SD) | 5.4 (2.3) | 4.5 (1.6)* | 4.8 (1.7) | 4.8 (1.5) | 4.8 (1.8) | |||||
| Median | 5.0 | 4.0 | 4.0 | 4.0 | 5.0 | |||||
| Min, max | 2, 12 | 3, 10 | 3, 12 | 3, 9 | 2, 12 | |||||
| MIC of levofloxacin for PA | ||||||||||
| Number of PA isolates tested | 140 | 152 | 148 | 152 | 592 | |||||
| MIC 50, μg/ml | 4 | 4 | 4 | 4 | 4 | |||||
| MIC 90, μg/ml | 16 | 32 | 16 | 16 | 16 | |||||
| Min, max | 0.25, 32 | 0.13, 128 | 0.13, 64 | 0.13, 64 | 0.13, 128 | |||||
| % Not susceptible to levofloxacin† | 68 | 60 | 53 | 62 | 61 | |||||
Empty returned vials were counted and compared with the number of vials that should have been used during the time frame of the study. Over the 28-day treatment period, 86.5% of the placebo group and 92.3 to 97.3% of MP-376 groups took more than 80% of the required doses. For the 240 mg groups, the time of nebulization averaged between 4 and 6 minutes.
Adjusted mean sputum PA density decreased from baseline for the patients taking MP-376 at Day 28 but increased for placebo-treated patients (Figure 2, top panel). At Day 28, the greatest treatment effect was observed in the MP-376 240 mg twice a day group (placebo, 0.23 log cfu/g sputum increase; MP-376 240 mg twice a day, 0.73 log decrease; treatment difference of −0.96 log10 cfu/g; 95% CI, −1.54 to −0.38; P = 0.001). More patients in the MP-376 240 mg groups experienced a significant change of greater than or equal to 1 log decrease in PA density compared with placebo (placebo, 8%; MP-376 240 mg every day, 32% [P = 0.004]; MP-376 240 mg twice a day, 36% [P = 0.004]). PA density returned toward baseline levels in all treatment groups by the end of follow-up (Day 56).
Figure 2. Changes in Pseudomonas aeruginosa (PA) density in sputum, FEV1, and Cystic Fibrosis Questionnaire—Revised (CFQ-R)-Respiratory scores. cfu = colony-forming units.
[More] [Minimize]Many patients had bacteria other than Pseudomonas cultured from their sputum at baseline. Nearly half of the patients had Staphylococcus aureus, whereas other pathogens, such as Stenotrophomonas maltophilia and Achromobacter xylosoxidans, were present in much smaller numbers. There was no consistent change in the number of patients with these organisms present during the study (see Table E2 in the online supplement), suggesting no selection of any pathogens in this brief treatment period. Also, whether or not S. aureus was present at baseline, the change in sputum PA density and percent change in FEV1 was similar within the treatment groups (data not shown). No correlation between baseline MIC values for levofloxacin against PA and change in sputum PA density and percent change in FEV1 at Day 28 was observed (combined Spearman correlation r = 0.18 and r = −0.0836, respectively; Figures E1 and E2). Importantly, there were no significant changes in levofloxacin MIC50 or MIC90 values for PA during the 28-day treatment or the follow-up period of the study (Table E3).
Mean FEV1 values improved with increasing doses of MP-376 and decreased in placebo recipients (Figure 2, middle panel). The mean changes in absolute FEV1 for the MITT population at Day 28 were −50, +40, +40, and +90 ml for the placebo, MP-376 120 mg every day, MP-376 240 mg every day, and MP-376 240 mg twice a day groups, respectively. Percent change from baseline in FEV1 at Day 28 for placebo and MP-376 240 mg twice a day were significantly different (placebo, −2.36%; MP-376 240 mg twice a day, 6.25%; treatment difference of 8.6%; 95% CI, 3.05–14.17; P = 0.003). There was still statistically significant improvement in FEV1 at Day 42 for the MP-376 240 mg twice a day group, but values returned to baseline by Day 56. More patients in the MP-376 treatment groups experienced a greater than 10% increase in adjusted FEV1 on Day 28 compared with the placebo group (placebo, 27%; MP-376 120 mg every day, 59%; MP-376 240 every day, 54%; MP-376 240 mg twice a day, 72% [P = 0.001 vs. placebo]). Results for other pulmonary function tests (FEV1 percent predicted, FVC, and forced expiratory flow, midexpiratory phase [FEF25–75%]) followed a similar, dose-dependent trend (Figures E3–E6). As with FEV1, the relative change in percent predicted FEV1 values at Day 28 for placebo and MP-376 240 mg twice a day were significantly different (placebo, −2.4%; MP-376 240 mg twice a day 8.6%; treatment difference of 10.9%; P = 0.0008).
CFQ-R–Respiratory symptom scores improved in MP-376–treated patients (Figure 2, bottom panel), with the changes being statistically significant in the MP-376 240 mg twice a day group at Day 14, but not at Day 28. At Day 28, placebo patients experienced a mean decrease of 0.44 points, whereas the MP-376 240 mg twice a day patient group showed improvements from baseline of 4.06 points. Although the treatment difference of 4.5 points was not statistically significant (P = 0.22), it exceed the prospectively defined minimal clinically important difference of 4 points (25). During the 28-day treatment period, 43 to 49% of MP-376–treated patients experienced increases of 4 or more points in respiratory scores compared with 30% in the placebo group. By day 56, scores had returned to near-baseline levels.
MP-376 treatment resulted in a reduction in the need for other antipseudomonal antimicrobials compared with placebo over the 56-day study period (Figure 3). A clinically and statistically significant reduction in risk for needing additional antibiotics was observed for the MP-376 120 mg every day (71%, P = 0.007), 240 mg every day (61%, P = 0.021), and 240 mg twice a day (79%, P < 0.001) treatment groups, respectively. The median time to antibiotic need could not be determined for any group; however, the 25th percentile was 31 days for the placebo group compared with 56 days and 59 days for the MP-376 240 mg every day and twice a day groups, respectively.
Figure 3. Time to need for additional antipseudomonal antibiotics. BID = twice a day; HR = hazard ratio; QD = every day.
[More] [Minimize]The incidence of adverse events was similar for patients receiving MP-376 and placebo during the 28-day treatment period. (Table 2) On-treatment adverse events were generally mild to moderate. Those events reported with the highest frequency in MP-376–treated patients were complaint about taste, (45 patients; 40%), cough (18 patients; 16%), and headache (9 patients; 8%). The only adverse event that was statistically more prevalent in the MP-376 groups was the complaint of taste, and although all taste events were believed by the investigators to be related to study drug, only five (3.3%) and three (2.0%) cough and headache episodes, respectively, were considered related to study drug. Taste complaints were predominantly mild in severity, and no patients discontinued treatment or withdrew from the study because of it. Two cases of drug intolerance in patients receiving MP-376 led to early discontinuation from the study at Day 1; a third case of drug intolerance was reported by a patient given MP-376 240 mg every day who experienced 20% or greater decline in FEV1 but remained asymptomatic and continued in the study. There was a total of four serious adverse events during the 28-day treatment period: two cases of acute pulmonary exacerbation in the placebo group, one occurrence of bronchitis in another placebo patient, and one case of appendicitis unrelated to study drug in a patient administered MP-376 120 mg every day. There were no complaints related to joints, tendons, or musculoskeletal system.
Placebo (n = 37) | MP-376 120 mg Every Day (n = 38) | MP-376 240 mg Every Day (n = 37) | MP-376 240 mg Twice a Day (n = 39) | MP-376 Pooled (n = 114) | |
|---|---|---|---|---|---|
| Patients reporting≥ 1 AE | 27 (73.0) | 27 (71.1) | 31 (83.8) | 26 (66.7) | 84 (73.7) |
| Patients reporting≥ 1 SAE | 3 (8.1) | 1 (2.6) | 0 (0.0) | 0 (0.0) | 1 (0.9) |
| Cough | 4 (10.8) | 6 (15.8) | 6 (16.2) | 6 (15.4) | 18 (15.8) |
| Diarrhea | 2 (5.4) | 2 (5.3) | 4 (10.8) | 1 (2.6) | 7 (6.1) |
| Disease progression* | 7 (18.9) | 2 (5.3) | 1 (2.7) | 2 (5.1) | 5 (4.4) |
| Dysgeusia† | 1 (2.7) | 14 (36.8) | 18 (48.6) | 13 (33.3) | 45 (39.5) |
| Headache | 0 | 4 (10.5) | 1 (2.7) | 4 (10.3) | 9 (7.9) |
| Hemoptysis | 4 (10.8) | 1 (2.6) | 2 (5.4) | 1 (2.6) | 4 (3.5) |
| Intolerability | 0 | 1 (2.6) | 1 (2.7) | 1 (2.6) | 3 (2.6) |
In general, laboratory parameters and ECG results remained stable through the study, and any shifts from baseline did not correlate with receipt of placebo or dose of MP-376. Twelve patients (8%) required hospitalization during the study, with no differences among treatment groups in hospitalizations.
This study demonstrates the efficacy and safety of aerosolized MP-376 compared with placebo in a population of patients with CF receiving extensive treatment for maintenance of respiratory health. MP-376 significantly reduced the density of PA in sputum, the primary endpoint of the study, after 28 days at all doses tested, consistent with its antibacterial effect. MP-376 also substantially reduced the need for systemic or inhaled antipseudomonal antimicrobials, and produced improvements in pulmonary function, specifically FEV1, FVC, and FEF25–75%. An increase in the respiratory score of the CFQ-R was observed with MP-376 administration in the highest-dose group. After 28 days of treatment, the differences between the MP-376 240 mg twice a day group and the placebo group were statistically significant for all endpoints described above, except CFQ-R. There was a strong trend of greater improvement with increasing dose of MP-376 for most of these endpoints, consistent with a dose response. These improvements in clinical endpoints were seen despite the PA in the majority of the baseline sputum cultures having an MIC higher than 2 μg/ml for levofloxacin, demonstrating the irrelevance of parenteral breakpoints for resistance when using inhaled antibiotics (27).
Study conduct was very good, with only eight (5%) patients discontinuing the study, and MP-376 was found to be safe and generally well-tolerated. Most of the adverse events were mild or moderate in severity and did not increase in frequency or severity with increasing doses of MP-376. Although there was a high incidence of taste complaints, no patients discontinued from study drug or from the study due to these complaints. There were no treatment-related serious adverse events reported in any of theMP-376 groups. Other than complaints about the taste of MP-376, the adverse events noted during the study were typical for the underlying CF sinopulmonary disease. No significant increase in levofloxacin MICs in PA was observed after 28 days of exposure in any of the MP-376 or placebo groups.
It was important to design this study to include patients with significant prior exposure to other inhaled antibiotics to assess the treatment effect with MP-376. Recently published guidelines establish the long-term use of inhaled antibiotics as a standard of care for chronic PA infection (9, 10). Inhaled TIS and colistin have been used for many years, and AZLI was recently approved for treatment of chronic PA infection. It is also notable that these patients used other chronic medications, including dornase alfa, azithromycin, and inhaled hypertonic saline, all of which are now recommended for chronic use in patients with CF with PA (9). As these therapies have been incorporated into CF treatment regimens over the past few years, lung health has improved and there has been a lesser degree of improvement with added therapies; that is, the magnitude of the response to medications with respect to relevant endpoints, such as PA density and FEV1, has diminished compared with earlier studies of inhaled tobramycin when it was first introduced (28). Indeed, the recent pivotal studies of inhaled aztreonam, showed that those patients with more intensive treatment with chronic medications at baseline had less response to aztreonam with regard to P. aeruginosa density, FEV1, and CFQ-R respiratory scores compared with those patients on less-intensive baseline therapy (8, 29). Similarly, the effect of TIS on bacterial density was reduced in older, more antibiotic-exposed patients (7). The patients in the current study were an average 8 years older than those in the TIS study and had a more extensive exposure to chronic maintenance therapies compared with those reported in any other study of inhaled antibiotics. Despite this, MP-376 resulted in a significant reduction in PA density (the primary endpoint) and improvement in the secondary endpoints, adding confidence that MP-376 offers clinically important improvement for patients with CF who already take several therapies for the maintenance of lung health.
This study showed that MP-376 significantly reduced the proportion of subjects requiring additional systemic or inhaled antibiotics, with a 79% risk reduction being observed in the 240 mg twice a day group. The study period was too short to capture the median time to need for additional antibiotics; however, an extended follow-up period of greater than 28 days post study drug was considered too long to have patients off standard-of-care therapy. Prevention of exacerbations is a very important component in preserving lung function, as recent data demonstrate that lung function does not return to preexacerbation levels in about 25% of patients who experience an exacerbation (30).
Although use of aerosolized antibiotics for suppression of chronic airways infection is the standard of care for patients with CF, there is evidence that they are underused. TIS has been available since 1998, yet according to U.S. CF Registry data, one-third of eligible patients are not receiving long-term TIS therapy (11). Furthermore, of those patients who had TIS prescribed, almost 75% used two cycles or fewer (13). Possible explanations for this deviation from accepted guidelines include decreased clinical response (7, 14, 29), concerns about resistance or cumulative toxicity (31), drug intolerance, and treatment burden, specifically the 15- to 20-minutes per dose administration time. The recently approved inhaled aztreonam has a much shorter administration time but requires more frequent dosing than TIS. Inhaled colistimethate is recommended in the European consensus statement (10) but not in the U.S. guidelines, nor is it approved in the United States. Further treatment options are necessary to address the concerns of microbial resistance, new emerging organisms, loss of efficacy over time, and treatment burden.
Levofloxacin appears to have several pharmacologic properties that would be advantageous for treating CF airway infections. Although PA is the pathogen most frequently associated with pulmonary morbidity in CF, the microbiologic environment of the CF lung is complex, often including many microbe species, biofilm formation, and microenvironments with low oxygen tension. A series of in vitro studies demonstrated that levofloxacin was more potent than tobramycin, amikacin, or aztreonam when tested against clinical isolates of PA, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Burkholderia cepacia complex, and Staphylococcus aureus (sensitive and resistant to methicillin) (16). The activity of levofloxacin was not reduced by exposure to sputum from patients with CF, whereas tobramycin activity was significantly impaired (16). Pseudomonas biofilms did not affect the MIC of levofloxacin, whereas the MICs increased several-fold for tobramycin and aztreonam (16). Furthermore, although anaerobic conditions significantly reduced the potency of tobramycin, amikacin, and aztreonam, the potency of levofloxacin was relatively maintained (32). These data support the clinical findings that MP-376 has significant potential for the control of current and emerging CF pathogens. MP-376 also has features that reduce the time burden for patients with CF, including use of a fast, efficient, customized eFlow nebulizer (33) requiring only 4 to 6 minutes to nebulize a 240-mg dose. MP-376 is also provided as a premixed solution in single-use ampule that provides for patient convenience.
This large clinical study shows that MP-376 given for 28 days reduces PA density and the need for other antibiotics while improving respiratory symptoms and pulmonary function in heavily treated patients with CF. MP-376 was tolerated well and did not lead to increased levofloxacin resistance in sputum PA isolates. Further studies will be needed to define the appropriate strategy for incorporating MP-376 use into the long-term treatment of chronic airway infection in CF.
Principal Investigators (PI) and Study Coordinators (SC): United States: Valhalla, NY – PI: Allen Dozor; SC: Ingrid Gherson; Little Rock, AR – PI: Ariel Berlinski; SC: Patricia Brady; Park Ridge, IL – PI: Avery Stone; SC: Suellen Moen; Sacramento, CA – PI: Brian Morrissey; SC: Ellen Vlastelin; Orange, CA – PI: Bruce Nickerson; SC: NozomiYagi; Palo Alto, CA – PI: Carol Conrad; SC: Colleen Dunn, Zoe Davis; Tucson, AZ – PI: Cori Daines; SC: Osmara Molina; Las Vegas, NV – PI: Craig Nakamura; SC: Teresa Melvin, Ryan Yoshikawa; Columbia, SC – PI: David Brown; SC: Betty Johnson; Orlando, FL – PI: David Geller; SC: Bert Kesser, Angie Price; Memphis, TN – PI: Dennis Stokes; SC: Barbara Culbreath, Stefani Vatter; San Diego, CA – PI: Douglas Conrad; SC: Bobbie Munden; Kalamazoo, MI – PI: Douglas Homnick; SC: Nancy Wallace, Esther Wyman; Oakland, CA – PI: Gregory Shay; SC: Julie Lee; Cincinnati, OH – PI: James Acton; SC: Lorrie Duan; Oklahoma City, OK – PI: James Royall; SC: Jodie Groff; Philadelphia, PA - PI: Jeffrey Hoag; SC: Judy Hillman; Minneapolis, MN – PI: Joanne Billings; SC: Trisha Grover; Albany, NY – PI: Jonathen Rosen; SC: Kathy Mokhiber; Columbus, OH - PI: Karen McCoy; SC: Laura Raterman; Mobile, AL – PI: Lawrence Sindel; SC: Tony Cowan, Michelle Hemphill; Los Angeles, CA – PI: Marilyn Woo, Thomas Keens; SC: Lynn Fukushima, Kelsey Maloy; Miami, FL – PI: Matthias Salathe; SC: Fernando Cubillos; Pittsburgh, PA – PI: Patricia Dubin; SC: Elizabeth Hartigan, Sandy Hurban; Charleston, SC – PI: Patrick Flume; SC: Terry Byars; San Antonio, TX – PI: Peter Fornos; SC: Teresa Phillips; Tyler, TX – PI: Rodolfo Amaro-Glavez; SC: Jan Hoeft; Louisville, KY – PI: Ronald Morton; SC: Kara Richardson; Ann Arbor, MI – PI: Samya Nasr; SC: Dawn Kruse; Oklahoma City, OK – PI: Santiago Reyes; SC: Teresa Orf; Morristown, NJ – PI: Stanley Fiel; SC: Carol Cahill; Glenview, IL – PI: Steven Boas; SC: Clarice Jernagin; Salt Lake City, UT – PI: Ted Liou; SC: Kristyn Packer; Boston, MA – PI: Terry Spencer; SC: Erin Leone. Germany: Giessen – PI: Daniel Schuler, Christina Geidel; SC: Claudia Ruckes-Nilges; Berlin – PI: Doris Staab; SC: Christine Nagel; Tubingen – PI: Joachim Riethmuller; SC: Andrea Evers-Bischoff; Munchen – PI: Rainald Fischer; SC: Maria Kerscher; Frankfurt – PI: Thomas Wagner; SC: IngeWortmann; Gerlingen – PI: Martin Kohlhaeufl; SC: Iris Strecker; Kiel – PI: BurkhardBewig; SC: Sonja Rohweder; Essen – PI: Helmut Teschler; SC: Cordula Conrad – Kabbe. Netherlands: Groesbeek - PI: Monique Reijers; SC: FemkeCuppen; Amsterdam – PI: ElsWeersink; SC: Gerrit-Jan Illbrink.
The authors thank the patients and their families who participated in this study, as well as the principal investigators and study coordinators for each study site, as listed below. Statistical analyses were performed by Synteract, Carlsbad, CA. The authors also thank Dr. Alexandra Quittner for the use of the CFQ-R and the Protocol Review Committee of the Cystic Fibrosis Foundation Therapeutic Development Network for their thorough review of the protocol.
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