Tobramycin

Background: Cystic fibrosis (CF) is characterized by chronic pulmonary infection with acute pulmonary exacerbations (APEs) requiring IV antibiotic treatment. We report on a blinded comparative trial of IV meropenem (40 mg/kg to 2 g q8h) or ceftazidime (5 mg/kg to 2 g q8h), each of which was administered with IV tobramycin (at a serum peak of [greater than or equal to] 8 [micro]g/mL and a trough of < 2 [micro]g/mL), as treatment for CF patients with APEs.

Methods: Patients who were [greater than or equal to] 5 years of age who were infected with ceftazidime-susceptible Pseudomonas aeruginosa were stratified by lung function and randomized to treatment with meropenem/tobramycin or ceftazidime/tobramycin. Patients infected with Burkholderia cepacia complex or ceftazidime-resistant P aeruginosa were assigned to receive open-label meropenem/ tobramycin. Clinical response was assessed by spirometry to determine the change in percent predicted [FEV.sub.1] and by a clinical acute change score (ACS).

Results: One hundred two patients were randomized to meropenem/tobramycin (n = 50) or ceftazidime/tobramycin (n = 52). Nineteen patients received open-label meropenem/tobramycin. [FEV.sub.1] was improved at the end of treatment (EOT) with meropenem/tobramycin (mean [+ or -] SD] increase, 38.8 [+ or -] 52.3%) and with ceftazidime/tobramycin (mean increase, 29.4 [+ or -] 35.1%; p < 0.0001 vs baseline values). The proportion of patients with [greater than or equal to] 15% relative increase from baseline [FEV.sub.1] (satisfactory response) at day 7 was 62% for the meropenem/tobramycin group and 44% for the ceftazidime/tobramycin group (p = 0.04). The median time to [FEV.sub.1] response was 4 days for meropenem/tobramycin therapy vs 6 days for ceftazidime/tobramycin therapy. Similarly, [FEV.sub.1] improved in the open-label group (mean increase, 12.5 [+ or -] 25.7%; p = 0.05). ACS improved in all three groups at EOT (p < 0.0001 vs baseline values).

Conclusions: Therapy with both meropenem/tobramycin and ceftazidime/tobramycin improved pulmonary and clinical status and reduced sputum bacterial burden in CF patients with APEs. A larger proportion of patients receiving meropenem/tobramycin therapy demonstrated a satisfactory [FEV.sub.1] response at day 7. Resistant P aeruginosa emerged infrequently during treatment with both regimens.

Key words: acute pulmonary exacerbation; ceftazidime; cystic fibrosis; meropenem

Abbreviations: ACS = acute change score; APE = acute pulmonary exacerbation; CF = cystic fibrosis; EOT = end of treatment; MIC = minimum inhibitory concentration

**********

Worldwide, an estimated 50,000 people have cystic fibrosis (CF). (1) CF is characterized by chronic pulmonary infections with periodic exacerbations that require treatment with IV antibiotics. More than 90% of deaths in patients with CF can be attributed to loss of lung function. (2) In fact, the relative risk of death for patients with CF doubles with each 10% loss of [FEV.sub.1] percent predicted. (3)

Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa are the most frequently isolated organisms during the first decade of life, but P aeruginosa predominates (80% of patients) in adolescents and adults. (1) P aeruginosa respiratory infection is a major predictor of morbidity and mortality in children with CF. (4) Burkholderia cepacia complex is implicated in a much lower proportion of pulmonary bacterial infections (3.1%) (1) and is often intrinsically resistant to the antimicrobial agents commonly used to treat infections in patients with CF, including colistin, aminoglycosides, and ciprofloxacin. (5) Thus treatment options are limited for infections caused by this pathogen.

The use of IV antimicrobial agents to treat acute pulmonary exacerbations (APEs) in patients with CF has become standard practice and has contributed to a dramatic increase in life expectancy in the past few decades. (6) Antipseudomonal agents that are available for treatment include extended-spectrum penicillins, cephalosporins, aminoglycosides, fluoroquinolones, polymixins, and monobactams. Treatment with an aminoglycoside in combination with a [beta]-lactam is the usual first-line therapy for APE in patients with CF. (7) Ceftazidime and tobramycin combination therapy is considered by some clinicians to be the clinical standard. (8) However, no trial has demonstrated a clinically significant advantage of any particular combination regimen over another, (5) and no consensus on a specific aminoglycoside [beta]-lactam combination treatment regimen exists among clinicians. (9)

The broad-spectrum carbapenem meropenem possesses potent activity against both P aeruginosa and B cepacia complex. (10) Data from a preliminary trial demonstrated that meropenem was well-tolerated and effective in the treatment of APE in patients with CF, (11) and there is further documented evidence of its efficacy in compassionate usage studies. (12,13) Furthermore, the use of meropenem, 40 mg/kg IV q8h, which is the approved dosage for the treatment of meningitis, in combination with an aminoglycoside may help to limit the emergence of antimicrobial resistance in P aeruginosa during treatment. (14)

Based on these preliminary data, we performed an investigator-blinded, randomized clinical trial to compare the efficacy, safety, and tolerability of therapy with meropenem in combination with tobramycin, compared to therapy with ceftazidime plus tobramycin in patients with CF experiencing an APE who were known to be infected with P aeruginosa. We also assessed the efficacy and safety of open-label treatment with meropenem plus tobramycin in patients with an APE who were known to be infected with B cepacia complex or ceftazidime-resistant P aeruginosa. We report on the efficacy of both study regimens in improving pulmonary function, general clinical status, and sputum bacterial burden, as well as on the impact of both regimens on the emergence of antibiotic resistance during treatment.

MATERIALS AND METHODS

Patients

Patients with CF (which was diagnosed on the basis of a prior elevated sweat chloride level or an abnormal CF transmembrane regulator genotype) who were [greater than or equal to] 5 years of age and were experiencing an APE were eligible for enrollment in the study if they had had a recent sputum culture, generally obtained within 1 month prior to study enrollment, with isolation of P aeruginosa and/or B cepacia complex.

An APE was defined by the presence of at least 5 of 10 of the following clinical signs or symptoms: increase in the frequency of productive cough; increase in the volume of and change in the appearance of sputum; increase in respiratory rate; appearance of dyspnea; decreased breath sounds on physical examination; new infiltrates seen on chest radiograph; deterioration in pulmonary function test results; decreased appetite or weight loss; decreased activity; and decreased exercise tolerance. (2,15) During treatment, patients received physiotherapy and other supportive therapy in accordance with the general standard of care required for patients with CF at each participating center. However, therapy with nonstudy antimicrobial agents, including aerosolized tobramycin, was discontinued prior to study treatment.

This study was conducted in accordance with the recommendations found in the Helsinki Declaration of 1975. The study protocol and informed consent were approved by the Institutional Review Board for Human Studies at each site. Informed consent was obtained from each subject.

Study Design

This was a multicenter study that included a randomized investigator-blinded comparative trial and a noncomparative, open-label study. The randomized trial compared the efficacy, tolerability, and pharmacokinetics of meropenem (40 mg/kg [to a maximum of 2 g] q8h) or ceftazidime (50 mg/kg [to a maximum of 2 g] q8h), each of which was administered in combination with IV tobramycin (dosage to maintain serum peak levels at [greater than or equal to] 8 [micro]g/mL and the trough at < 2 [micro]g/mL), as treatment for CF patients infected with P aeruginosa and experiencing an APE.

Quantitative cultures of expectorated sputum or cultures from deep throat swabs were obtained at the time of study entry in order to assess bacteriologic outcomes. Patients infected with ceftazidime-susceptible and meropenem-susceptible strains of P aeruginosa were randomized to the comparative trial. Patients known to be infected with B cepacia complex or ceftazidime-resistant P aeruginosa were assigned to open-label treatment with IV meropenem in combination with IV tobramycin (Fig 1). In the comparative trial, patients were stratified according to disease severity based on their [FEV.sub.1] prior to study entry, as follows: mildly affected ([FEV.sub.1] [greater than or equal to] 70% predicted); moderately affected ([FEV.sub.1] [greater than or equal to] 40 to 69% predicted); and severely affected ([FEV.sub.1] < 40% predicted).

[FIGURE 1 OMITTED]

Antibiotic Treatment

Meropenem (AstraZeneca; Wilmington, DE), 40 mg/kg IV up to a maximum dose of 2 g, and ceftazidime, 50 mg/kg IV up to a maximum dose of 2 g, were administered every 8 h. Tobramycin was administered IV in a dosage regimen adjusted to yield a peak tobramycin serum concentration of [greater than or equal to] 8 [micro]g/mL and a trough concentration of < 2 [micro]g/mL. Each antimicrobial infusion was administered over a 30-min period.

The expected duration of trial therapy was 14 days. For patients whose treatment lasted < 14 days, the end of treatment (EOT) was defined as the day the final dose was administered. For patients with treatment duration in excess of 14 days (based on the physician's assessment of clinical response), data from the day 14 assessments were used for the EOT analyses. Follow-up assessment was performed 2 to 4 weeks after the discontinuation of trial therapy.

Pulmonary Function Measurement

Pulmonary function was assessed at the time of the pretreatment visit (baseline), daily during treatment, and at EOT using a spirometer (Asthmalog; Datalog, Inc; Stillwater, MN). The following information was collected: FVC; [FEV.sub.1]; [FEV.sub.1]/FVC ratio; peak expiratory flow; forced expiratory flow; FVC percent predicted; and [FEV.sub.1] percent predicted using the equation of Knudson et al. (16) Results were transmitted by telephone to Datalog, Inc, and were reported in the electronic database as absolute numerical values. The best result from triplicate determinations each day was incorporated into the analysis.

For data analysis, the change in [FEV.sub.1] during study treatment was expressed as the relative percentage change from baseline in the [FEV.sub.1] percent predicted. For comparison, [FEV.sub.1] data were also analyzed as the absolute change from baseline in [FEV.sub.1] percent predicted. The calculations to obtain this information were as follows:

% predicted [FEV.sub.1] = (recorded [FEV.sub.1]/predicted [FEV.sub.1]) x 100

Relative percentage change in % predicted [FEV.sub.1] = (% predicted [FEV.sub.1] at assessment - % predicted [FEV.sub.1] pretreatment) x 100 / % predicted [FEV.sub.1] pretreatment

Absolute change in % predicted [FEV.sub.1] = (% predicted [FEV.sub.1] at assessment - % predicted [FEV.sub.1] pretreatment)

The primary efficacy variable was the relative percentage change from baseline in [FEV.sub.1] percent predicted at the EOT (or after 14 days of treatment for those patients in whom antibiotic therapy was continued for > 14 days). In both the investigator-blinded, comparative trial and the open-label study, patients were defined as treatment responders if a [greater than or equal to] 15% relative increase in [FEV.sub.1] percent predicted from baseline was observed. Improvements of this magnitude have been associated with decreased perception of dyspnea and increased overall well-being in other studies of CF patients experiencing APEs, (17,18) while exceeding the intraindividual coefficient of variation for [FEV.sub.1] determinations at a single sitting. (19,20) In addition, the median time required for treatment response was analyzed.

Acute Change Score

The acute change score (ACS) as proposed by Smith et all (15) was evaluated at study enrollment, on day 7, and at EOT. Patients were graded according to the investigator's clinical assessment of activity level, cough, appetite, chest examination, weight fluctuations, and respiratory effort. Each category was scored on a scale of 1 (least severe) to 5 (most severe). A decrease in score denoted improvement, and patients with a reduction of [greater than or equal to] 15% in their ACS were classified as responders:

% change in ACS = (ACS at assessment - ACS pretreatment) x 100 / ACS pretreatment

Exacerbation-Free Interval

Clinical follow-up continued at each patient's treatment clinic as per the clinic routine. The time from EOT until the next APE was recorded and compared with the average APE-free period in the 3 years prior to study enrollment. For patients with no reported APEs, the number of days reported until a new APE during extended follow-up was censored at the end of the study (December 31, 2001).

Sputum Bacterial Burden

Sputum samples for culture were collected for each patient before the start of therapy, weekly during study treatment, at study completion, and 14 to 30 days after the completion of study treatment (ie, the follow-up period). Sputum samples were obtained by deep expectoration and deep throat swabbing (if deep expectoration was not possible) and were shipped on frozen ice packs to the CF Referral Center for Susceptibility and Synergy Studies at Columbia University by overnight express. On arrival in the core laboratory, specimens were plated on selective media suitable to enhance the recovery of P aeruginosa, B cepacia complex, Aspergillus spp, Stenotrophomonas maltophilia, and H influenzae or other relevant pathogens.

Samples were assessed for suitability for culture by visual inspection of quantity and by Gram stain (ie, > 10 polymorphonuclear cells and < 10 squamous cells per low-power field). The susceptibility of infecting organisms to meropenem, ceftazidime, or tobramycin was determined by minimum inhibitory concentration (MIC) using the broth dilution method according to the National Committee of Clinical Laboratory Standards recommendations. (21) MICs were reported for P aeruginosa subtypes and B cepacia complex. The breakpoint for resistance was considered to be > 16 [micro]g/mL for ceftazidime, > 8 [micro]/mL for meropenem, and > 8 [micro]g/mL for tobramycin. In addition, the oxacillin susceptibility of all isolates of S aureus was determined.

A patient was defined as a bacteriologic success at day 7, the EOT, or at follow-up if that patient demonstrated a [greater than or equal to] 2 [log.sub.10] reduction between the result of the baseline culture and the culture obtained on the day of assessment of the sputum sample (in colony-forming units per gram). In addition, the proportion of patients with isolates of P aeruginosa or B cepacia complex demonstrating resistance to meropenem and/or ceftazidime at study entry, day 7, EOT, and follow-up was analyzed.

Safety and Tolerability

Clinical laboratory assessments, physical examinations, and vital sign measurements were performed before treatment, on day 7, and at EOT to evaluate the safety and tolerability of study treatment. Adverse events were assessed by severity and by their relationship to the study treatment. Adverse events with an incidence of > 1% or those judged (by the investigator) to be related to treatment were analyzed.

Statistical Analysis

For each outcome, the analysis set included all eligible patients who had received at least 4 days of study treatment and for whom the required measurements or cultures were obtained at baseline, on treatment day 7, and at EOT. Patients were excluded from the analysis of quantitative culture results if they had had no organism isolated or quantified at baseline, if no culture sample was obtained at day 7 or EOT, or if the initial culture was obtained from a deep throat swab (Table 1).

Within-group changes from baseline were analyzed using paired t tests or Wilcoxon rank sign tests in both the comparative trial and the open-label study. In the open-label study and in the comparative trial, it was postulated that there would be a difference in [FEV.sub.1] percent predicted and ACS of > 15% from baseline within each treatment group. The sample size necessary to detect a 15% change from baseline values at study enrollment was calculated using a one-sample t test. There were sufficient patients recruited into the treatment groups to detect a difference from baseline in primary and secondary outcome measures based on the initial power calculations with a power of > 80%.

For the comparative trial, analysis of variance was used to assess treatment differences and logistic regression was used to assess responder rate differences between treatments. The final sample size in the comparative trial was adequate to provide sufficient power such that a difference of 15% between the two groups would achieve statistical significance at an ct level of 0.05 and a power of 0.8 using a two-sample t test. Survival analysis Kaplan-Meier descriptive statistics were used to assess the time to a [greater than or equal to] 15% increase in [FEV.sub.1], and descriptive statistics and within-group t tests (comparative trial) were used to determine the microbiological response. Safety data were summarized using descriptive statistics. A statistical software package (SAS; SAS Institute; Cary, NC) was used to analyze the study data.

RESULTS

Patient Disposition

One hundred twenty-one CF patients with APEs were enrolled into this study at 16 sites in the United States between August 1997 and December 2001 (Fig 1). One hundred two patients were enrolled into the comparative trial: 50 patients received meropenem/tobramycin and 52 received ceftazidime/tobramycin. Nineteen patients with a recent antecedent sputum culture revealing infection with B cepacia complex or ceftazidime-resistant P aeruginosa were assigned to open-label treatment with meropenem plus tobramycin.

Demographics and Study Treatment

In the open-label study and in both treatment groups in the comparative trial, patients' baseline demographic characteristics and severity of illness (assessed by baseline [FEV.sub.1]) were well-matched (Table 2). The mean duration of treatment was 13.5 days (SD, 4.1 days) for meropenem/tobramycin recipients and 14.1 days (SD, 3.3 days) for ceftazidime/ tobramycin recipients in the comparative trial, and 15.6 days (SD, 5.1 days) for meropenem/tobramycin recipients in the open-label study. The mean durations of chest physiotherapy, bronchodilator therapy, and hospitalization were similar in both treatment groups in the comparative trial.

Pulmonary Response

Change in [FEV.sub.1]: Pulmonary function, expressed as the absolute change in [FEV.sub.1] percent predicted, significantly improved between baseline and the EOT in the open-label study and in the two comparative treatment groups. In the open-label study, the mean ([+ or -] SD) [FEV.sub.1] increased from 50.2 [+ or -] 28.9% predicted at baseline to 57.7 [+ or -] 37.5% predicted at the EOT (p = 0.03). In the comparative trial, the mean [FEV.sub.1] for ceftazidime/tobramycin patients increased from 44.7 [+ or -] 19.3% predicted to 55.8 [+ or -] 22.1% predicted (p < 0.0001), and for meropenem/tobramycin patients it increased from 47.1 [+ or -] 20.1% predicted to 60.9 [+ or -] 25.5% predicted between baseline and the EOT (p = 0.0002). Thus, a significant treatment effect was observed for all three groups of patients.

Expressed as the relative percentage change from the baseline [FEV.sub.1] percent predicted, meropenem/ tobramycin-treated patients in the comparative trial exhibited a 32.4 [+ or -] 47.9% mean improvement at day 7 vs a 19.8 [+ or -] 32.6% improvement in ceftazidime/ tobramycin patients (p = 0.07). The majority of improvement in [FEV.sub.1] was observed during the initial 7 days of antibiotic treatment in all treatment groups (Table 3). At the EOT, the relative mean change from baseline in [FEV.sub.1] was 12.5 [+ or -] 25.7% in the open-label study and 38.8 [+ or -] 52.3% for meropenem/ tobramycin-treated patients and 29.4 [+ or -] 35.1% (p < 0.001) for ceftazidime/tobramycin-treated patients in the comparative trial.

Satisfactory Pulmonary Response: A satisfactory response in pulmonary function was defined as a [greater than or equal to] 15% relative increase in the [FEV.sub.1] from baseline. In the comparative trial, for all disease severity strata combined, the proportion of patients with a [greater than or equal to] 15% relative increase in [FEV.sub.1] at day 7 was significantly greater with meropenem/tobramycin than with ceftazidime/tobramycin (62% vs 44%, respectively; p = 0.04) [Fig 2]. Furthermore, the median time for 50% of patients to experience a [greater than or equal to] 15% relative increase in [FEV.sub.1] was shorter for the meropenem/ tobramycin group (4 days) than for ceftazidime/ tobramycin group (6 days) [Fig 3]. By the EOT, 64% of meropenem/tobramycin-treated patients and 58% of ceftazidime/tobramycin-treated patients in the comparative trial demonstrated a satisfactory pulmonary response. Improvement in pulmonary function was observed in all strata of disease severity in both of the comparative treatment groups (Table 4). In the open-label study, 6 of 18 evaluable patients demonstrated a satisfactory pulmonary response by the EOT.

[FIGURES 2-3 OMITTED]

Clinical Response

ACS: In the comparative trial, there were statistically significant reductions from baseline at day 7 and EOT in ACS for the meropenem/tobramycin group (44% and 50% reduction, respectively) and for the ceftazidime/tobramycin group (45% and 56% reduction, respectively), indicating clinical improvement in both treatment groups at both assessments (p < 0.001). By the EOT, 96% of meropenem-treated patients and 92% of ceftazidime-treated patients were clinical responders, which was defined as a [greater than or equal to] 15% decrease in the ACS. Changes from baseline values of similar magnitude were observed in patients with mild, moderate, and severe chronic lung disease (data not shown).

Among open-label meropenem/tobramycin patients, there was a similar reduction in ACS at day 7 and EOT (37% and 46% reduction, respectively; p < 0.0001 vs baseline for both). By the EOT, 95% of patients were classified as responders.

Exacerbation-Free Interval: After the completion of study treatment, subjects were followed up until they experienced an APE or until December 31, 2001, if no exacerbation was documented. In the comparative trial, 33 meropenem/tobramycin-treated patients experienced an APE during follow-up, with a median time to new APE (ie, from EOT through extended follow-up) of 176 days. Thirty-eight of the ceftazidime/tobramycin-treated patients experienced an APE during follow-up with a median time to a new APE during extended follow-up of 207 days. The difference between the two groups did not reach statistical significance.

Among the open-label patients, most of whom were chronically infected with B cepacia complex, 12 of 19 patients (63%) experienced an APE during follow-up. The median time to the next APE in this group of patients was 136 days.

Microbiological Response

Sputum Bacterial Burden: In the comparative trial, 91 of 102 patients (89%) were culture-positive for one or more strains of P aeruginosa at study entry. Mucoid strains of P aeruginosa were isolated from 87 of 102 patients (85%), and nonmucoid strains were isolated from 57 of 102 patients (56%). Polymicrobial infection was documented in 70% of patients. The mean sputum bacterial burden at study enrollment was 5.98 [+ or -] 2.85 [log.sub.10] cfu/g sputum for ceftazidime-treated patients and 5.98 [+ or -] 2.52 [log.sub.10] cfu/g sputum for meropenem-treated patients.

Among the 19 patients entered into the open-label study, B cepacia complex was isolated from 14 patients and mucoid and nonmucoid strains of P aeruginosa were isolated from 11 patients. Polymicrobial infection was documented in 68% of open-label patients. The mean sputum bacterial burden at study enrollment was 7.66 [+ or -] 1.99 [log.sub.10] cfu/g sputum among these patients.

A statistically significant decrease from baseline sputum bacterial burden was observed among open-label patients and among patients in both comparative treatment groups at day 7 and at the EOT (Fig 4). In the comparative trial, both treatment groups were associated with treatment effects of similar magnitudes. For P aeruginosa, at the EOT the mean [log.sub.10] decreases in bacterial burden were -3.5 and -3.6, respectively, for the ceftazidime-plus-tobramycin treatment group (p < 0.0001) and the meropenem-plus-tobramycin treatment group (p < 0.0001).

[FIGURE 4 OMITTED]

Similarly, in the open-label study, a statistically significant decrease from baseline in sputum bacterial burden was observed at the EOT (mean [log.sub.10] change, -2.8; p = 0.008). For B cepacia complex, treatment with meropenem plus tobramycin was associated with a mean change from baseline of -1.8 [log.sub.10] at the EOT (p = 0.02). A similar trend was noted for patients with P aeruginosa, but the magnitude of the mean log change (reduction) in bacterial density was much greater. By the EOT, the mean [log.sub.10] change from baseline in P aeruginosa bacterial burden was -5.6 and was statistically significant (p = 0.04). In both the open-label and comparative treatment groups, sputum bacterial burden showed a trend back toward baseline values after the discontinuation of antibiotic treatment (data not shown).

Proportion of Patients With [greater than or equal to] 2 [log.sub.10] Decrease in Sputum Bacterial Burden: A satisfactory microbial response was defined as [greater than or equal to] 2 [log.sub.10] reduction in sputum bacterial burden between the baseline evaluation and the EOT. In the comparative treatment groups, 76% of both ceftazidime/tobramycin-treated patients and meropenem-tobramycin-treated patients demonstrated at least a 2 [log.sub.10] decline in colony-forming units per gram of sputum of P aeruginosa at the EOT. Among patients in the open-label study, the sputum bacterial burden decreased by at least 2 [log.sub.10] in 9 of 16 patients (56%) with evaluable quantitative cultures at both study entry and the EOT. In all three of the treatment groups, this degree of decline in sputum bacterial burden was maintained in only 26 to 31% of patients at the follow-up evaluation, which is consistent with the regrowth of the pathogens after the cessation of antibiotic therapy.

Expression of Antibiotic Resistance During Treatment: The MIC for ceftazidime, meropenem, and tobramycin was determined for all sputum isolates of P aeruginosa and B cepacia complex recovered at pretreatment, day 7, the EOT, and at the follow-up assessment. In the comparative trial, 13 of 51 ceftazidime-treated patients demonstrated the presence of at least one ceftazidime-resistant strain of P aeruginosa at trial entry. In contrast, 3 of 50 meropenem-treated patients in the comparative trial yielded a meropenem-resistant organism at entry. In both treatment groups, the isolation of ceftazidime-resistant or meropenem-resistant strains of P aeruginosa during antibiotic treatment was uncommon (1 of 50 ceftazidime/tobramycin patients and 0 of 47 meropenem/tobramycin patients at the EOT) [Table 5].

A similar pattern was observed in the open-label study. Six of 18 patients demonstrated at least one bacterial strain that was resistant to meropenem at pretreatment, including 5 of 14 strains of B cepacia complex. However, sputum cultures from 0 of 18 patients obtained at the EOT yielded meropenem-resistant isolates. In all three treatment groups, sputum cultures obtained at the follow-up evaluation revealed the presence of organisms resistant to the treatment of a [beta]-lactam antibiotic in approximately the same number of patients as was observed at study entry.

Overall Safety and Tolerability

Safety data from all enrolled patients who received at least one dose of study medication demonstrated that there was a similar proportion of patients with adverse events and treatment-related adverse events in both treatment groups (Table 6). No major differences were observed in the types or severity of individual adverse events that occurred.

Adverse events led to the withdrawal of three patients receiving meropenem/tobramycin and two receiving ceftazidime/tobramycin. Among the meropenem-treated patients, the reported adverse events leading to withdrawal were as follows: fever and lymphadenopathy (not considered to be treatment-related); pneumonitis exacerbation with headache, nausea, and vomiting; and elevated liver function test results (ie, alkaline phosphatase, serum glutamic pyruvic transaminase, and serum glutamic oxaloacetic transaminase). The investigator considered the adverse events in the latter two patients to be treatment-related. Two ceftazidime/tobramycin-treated patients were withdrawn from the study due to adverse events that were considered as probably related (pharyngitis) and possibly related (headache) to the study treatment. No seizures and no deaths occurred during this study.

DISCUSSION

This prospective clinical trial examined the efficacy of parenteral combination antibiotic therapy in the treatment of APEs in patients with CF who were known to be infected with B cepacia complex or ceftazidime-resistant P aeruginosa (ie, the open-label study), or meropenem-sensitive and ceftazidime-sensitive P aeruginosa (ie, the investigator-blinded, randomized, comparative trial). The trim enrolled 121 patients, making it one of the largest prospective trials of APEs in CF patients reported to date. The prospective design of the study allowed the enrollment of patients meeting a predefined definition of APE and the randomization to treatment based on known antecedent respiratory microbiology. In addition, the electronic capture of pulmonary function test results by a central laboratory utilizing identical equipment at all sites and the use of a central reference microbiology laboratory allowed the integration of results across multiple study sites.

In the randomized, comparative trial, treatment with either meropenem or ceftazidime, each in combination with IV tobramycin, was associated with a significant improvement from baseline in pulmonary function, clinical status, and sputum bacterial burden. The magnitude of the changes observed and the proportion of patients meeting the definition of a satisfactory response for each efficacy outcome at the EOT were similar for the meropenem and ceftazidime treatment groups. However, at day 7 meropenem-treated patients demonstrated a somewhat larger relative change from baseline in [FEV.sub.1] percent predicted and a larger proportion meeting the definition of a satisfactory pulmonary response than ceftazidime-treated patients. Furthermore, the median time to achieve a satisfactory pulmonary response was shorter for patients receiving meropenem/tobramycin (4 days) than for those receiving ceftazidime/tobramycin (6 days), suggesting a more rapid clinical response with meropenem-based therapy.

In the open-label study, treatment with the combination of meropenem plus IV tobramycin was also associated with significant improvement from baseline in pulmonary function ([FEV.sub.1] percent predicted), clinical status (ACS), and sputum bacterial burden. As expected, the magnitude of the change from baseline in [FEV.sub.1] predicted (13% improvement) during treatment was small, which is consistent with the advanced lung disease and poor prognosis for the patients with B cepacia complex. (5,22) Consistent with this was the observation that only 54% of these patients met the criterion for a satisfactory microbiological response for this organism, and these patients had a shorter median time to the next APE compared with those infected with antibiotic-susceptible P aeruginosa.

The relationship between antibiotic susceptibility and clinical response during the treatment of APEs has been questioned. (23) The emergence of antimicrobial resistance is a major challenge in the treatment of patients with CF. (24-26) In the current prospective study, the combination of either meropenem or ceftazidime with tobramycin was highly effective in suppressing the emergence of antibiotic-resistant P aeruginosa during treatment. Despite the rebound in sputum bacterial burden toward baseline levels after the cessation of antibiotic therapy, the number of patients with ceftazidime-resistant or meropenem-resistant organisms at the follow-up assessment was similar to that observed at trial entry. Similarly, 0 of 14 open-label patients who were culture-positive for B cepacia complex at study entry demonstrated meropenem-resistant strains at the EOT. The reappearance of resistant organisms at the follow-up assessment in previously colonized patients was observed, however.

Safety data from this study demonstrated that both meropenem and ceftazidime, in combination with tobramycin, were well-tolerated with a notably low incidence of nausea and/or vomiting, diarrhea, and skin rashes. Despite the use of meropenem at a dose of 40 mg/kg IV every 8 h, no seizures were reported.

This study supports the utility of combination therapy with a [beta]-lactam plus an aminoglyeoside in the treatment of APEs in patients with CF. The excellent tolerability profile of meropenem, the relatively low level of resistance to this antibiotic by P aeruginosa, and the low potential for the emergence of resistance during the treatment of APEs make this antibiotic a good choice for the treatment of patients with CF.

APPENDIX: COORDINATING INVESTIGATORS FOR EACH STUDY SITE

Michael Konstan, MD, Rainbow Babies and Children's Hospital, Cleveland, OH; Frank J. Accurso, MD, The Childrens Hospital, Denver, CO; Daniel Caplan, MD, Emory Cystic Fibrosis Center, Atlanta, MD; Robert A. Schumacher, MD, Lebonheur Children's Medical Center, Memphis, TN; Philip Black, MD, The Children's Mercy Hospital, Kansas City, MO; David Orenstein, MD, Children's Hospital of Pittsburgh, Pittsburgh, PA; Karen McCoy, MD, Children's Hospital, Columbus, OH; John T. Wilson, MD, Louisiana State University Medical School, Schreveport, LA; Astryd A. Menendez, MD, Arkansas Children's Hospital, Little Rock, AR; Carlos Milla, MD, Pediatric Pulmonary & Critical Care Medicine, Mayo Memorial Building, Minneapolis, MN; Bruce Marshall, MD, Intermountain Cystic Fibrosis Center, University of Utah, Salt Lake City, UT, Jay Lieberman, MD, Miller Children's Hospital, Long Beach, CA; Dana Kissner, MD, Harper Hospital, Detroit, MI; Stanley B. Fiel, MD, MCP-Hahnemann University, Philadelphia, PA; Peter Adamson, MD, Children's Hospital of Philadelphia, Philadelphia, PA; Patricia Joseph, MD, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

ACKNOWLEDGMENT: The investigators thank the Cystic Fibrosis Foundation and Bonney Ramsey, MD, for their helpful comments concerning the design of this trial. The authors also wish to acknowledge the participation and support of the Meropenem CF Trial Group.

This research was supported in part by a grant from AstraZeneca Pharmaceuticals and in part by a Pediatric Pharmacology Research Unit grant from the National Institute of Child Health and Human Development (HD31323-12).

Manuscript received January 17, 2005; revision accepted March 17, 2005.

REFERENCES

(1) Cystic Fibrosis Foundation. Patient registry: 2002 annual report. Bethesda, MD: Cystic Fibrosis Foundation, 2003

(2) Ramsey B. Management of pulmonary disease in patients with cystic fibrosis. N Engl J Med 1996; 335:179-186

(3) Kerem E, Reisman J, Corey M, et al. Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992; 326:1187-1191

(4) Emerson J, Rosenfeld M, McNamara S, et al. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol 2002; 34:91-100

(5) Banerjee D, Stableforth D. The treatment of respiratory pseudomonas in cystic fibrosis: what drug and which way? Drugs 2000; 60:1053-1064

(6) Ratjen F. Changes in strategies for optimal antibacterial therapy in cystic fibrosis. Int J Antimicrob Agents 2001; 17:93-96

(7) Rajan S, Saiman L. Pulmonary infections in patients with cystic fibrosis. Semin Respir Infect 2002; 17:47-56

(8) Master V, Roberts GW, Coulthard KP, et al. Efficacy of once daily tobramycin therapy for acute pulmonary exacerbations of cystic fibrosis: a preliminary study. Pediatr Pulmonol 2001; 31:367-376

(9) Doring G, Conway SP, Heijerman HG, et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J 2000; 16:749-767

(10) Pfaller MA, Jones RN. A review of the in vitro activity of meropenem and comparator antimicrobial agents tested against 30,254 aerobic and anaerobic pathogens isolated world wide. Diagn Microbiol Infect Dis 1997; 28:157-163

(11) Byrne S, Maddison J, Connor P, et al. Clinical evaluation of meropenem versus ceftazidime for the treatment of Pseudomonas spp. infections in cystic fibrosis patients. J Antimicrob Chemother 1995; 36(suppl):135-143

(12) Hoiby N. Danish cystic fibrosis named patient report: Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Denmark. Wilmington, DE: AstraZeneca, 1996

(13) Newell P. International cystic fibrosis named patient report. Wilmington, DE: AstraZeneca, 1995

(14) Drusano GL. Prevention of resistance: a goal for dose selection for antimicrobial agents. Clin Infect Dis 2003; 36(suppl):S42-S50

(15) Smith AL, Redding G, Doershuk C, et al. Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis. J Pediatr 1988; 112:547-554

(16) Knudson RJ, Lebowitz MD, Holberg CJ, et al. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983; 127:725-734

(17) Ramsey BW, Astley sJ, Aitken ML, et al. Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis. Am Rev Respir Dis 1993; 148:145-151

(18) Ranasinha C, Assoufi B, Shak S, et al. Efficacy and safety of short-term administration of aerosofized human DNase I in adults with stable stage cystic fibrosis. Lancet 1993; 342:199-202

(19) Nickerson BG, Leman RJ, Gerdes CB, et al. Within-subject variability and percent change for significance of spirometry for normal subjects and in patients with cystic fibrosis. Am Rev Respir Dis 1980; 122:859-866

(20) Cooper PJ, Robertson CF, Hudson IL, et al. Variability of pulmonary function tests in cystic fibrosis. Pediatr Pulmonol 1990; 8:16-22

(21) National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial tests for bacteria that grow anaerobically: approved standard MT-A5. Wayne PA: National Committee for Clinical Laboratory Standards, 2000

(22) Isles A, Machisky I, Corey M, et al. Pseudomonas cepacia infection in cystic fibrosis: an emerging problem. J Pediatr 1984; 104:206-210

(23) Smith AL, Fiel S, Mayer-Hamblett N, et al. Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis. Chest 2003; 123:1495-1502

(24) Smith AL, Doershuk C, Goldmann D, et al. Comparison of a [beta]-lactam alone versus [beta]-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis. J Pediatr 1999; 134:413-421

(25) Ciofu O, Giwercman B, Pedersen SS, et al. Development of antibiotic resistance in Pseudomonas aeruginosa during two decades of antipseudomonal treatment at the Danish CF center. APMIS 1994; 102:674-680

(26) Saiman L, Mehar F, Niu W, et al. Antibiotic susceptibility of multiply resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis, including candidates for lung transplantation. Clin Infect Dis 1996; 23:532-537

(27) Pedersen SS, Pressler T, Jensen T, et al. Combined imipenem/cilastatin and tobramycin therapy of multiresistant Pseudomonas aeruginosa in cystic fibrosis. Antimicrob Chemother 1987; 19:101-107

(28) Livermore D. Of Pseudomonas, porins, pumps and carbapenems. J Antimicrob Chemother 2001; 47:247-250

(29) Kuti JL, Nightingale C, Knauft F, et al. Pharmacokinetic properties and stability of continuous-infusion meropenem in adults with cystic fibrosis. Clin Ther 2004; 26:493-501

Jeffrey L. Blumer, PhD, MD; Lisa Saiman, MD, MPH; Michael W. Konstan, MD; and David Melnick, MD ([dagger])

* From the Rainbow Babies and Children's Hospital (Drs. Blumer and Konstan), Case Western Reserve University School of Medicine, Cleveland, OH; Columbia University (Dr. Saiman), New York, NY; and AstraZeneca (Dr. Melnick), Wilmington, DE.

([dagger]) A complete list of coordinating investigators for each study site is located in the Appendix.

Dr. Blumer has served as a consultant for and received grant funding from AstraZeneca; Dr. Saiman has served on the speaker board for AstraZeneca, has received grant funding from AstraZeneca, and has written an invited review with honorarium from AstraZeneca; Dr. Konstan was a consultant for Datalog; Dr. Melnick is an employee of AstraZeneca.

Correspondence to: Jeffrey L. Blumer, PhD, MD, Tulane University Scnool of Medicine, 1430 Tulane Ave, SL-37, New Orleans, LA 70112; e-mail: jblumer@tulane.edu

transaminase.

COPYRIGHT 2005 American College of Chest Physicians
COPYRIGHT 2005 Gale Group