Abstract
Rationale: In experimental pneumonia, nebulization of antibiotics provides high lung tissue concentrations and rapid bacterial killing.
Objectives: To assess the efficacy and safety of nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa.
Methods: Forty patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa were included in a randomized comparative phase II trial. Twenty patients infected with susceptible or intermediate strains received nebulized ceftazidime (15 mg·kg−1·3 h−1) and amikacin (25 mg·kg−1·d−1). Seventeen patients infected with susceptible strains received intravenous ceftazidime (90 mg·kg−1·d−1, continuous administration) and amikacin (15 mg·kg−1·d−1). In three patients infected with intermediate strains, amikacin was replaced by ciprofloxacin (400 mg·12 h−1).
Measurements and Main Results: After 8 days of antibiotic administration, aerosol and intravenous groups were similar in terms of successful treatment (70 vs. 55%), treatment failure (15 vs. 30%), and superinfection with other microorganisms (15 vs. 15%). Antibiotic-induced changes in lung aeration, determined by computed tomography, were not different between groups (increase in gas volume, 159 ± 460 vs. 251 ± 583 ml; decrease in tissue volume, –58 [–77, 25] vs. –89 [–139, 5] ml). Acquisition of per-treatment antibiotic resistance was observed exclusively in the intravenous group. In the aerosol group, four patients infected with intermediate strains were successfully treated. Nebulization induced an obstruction of the expiratory filter in three patients. The obstruction caused cardiac arrest in one patient, who fully recovered after brief cardiopulmonary resuscitation.
Conclusions: Nebulization and intravenous infusion of ceftazidime and amikacin provide similar efficiency for treating ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Nebulization is efficient against intermediate strains and may prevent per-treatment acquisition of antibiotic resistance.
In experimental inoculation pneumonia, nebulization of antibiotics provides high lung tissue concentrations and rapid bacterial killing.
Nebulized ceftazidime and amikacin provide clinical cure of ventilator-associated pneumonia caused by Pseudomonas aeruginosa, including strains with decreased susceptibility to one or both antibiotics, and may prevent per-treatment acquisition of antibiotic resistance.
Ventilator-associated pneumonia (VAP) caused by Pseudomonas aeruginosa (P. aeruginosa) is a difficult-to-treat infection associated with a high rate of recurrence and frequent selection for new resistance to antibiotics despite adequate initial antimicrobial therapy (1–3). Although ceftazidime is a cephalosporin whose activity is specifically directed against P. aeruginosa, impaired susceptibility of P. aeruginosa to ceftazidime is constantly on the rise (4, 5). The emergence of antibiotic resistance among isolates of P. aeruginosa is associated with a longer duration of hospitalization (6).
Nebulization of antibiotics offers the possibility of delivering high lung tissue concentrations of antibiotics in normal and infected lungs (7, 8). In experimental models, single daily nebulization of amikacin, a concentration-dependent antibiotic, provides rapid and efficient bacterial killing in piglets with Escherichia coli inoculation pneumonia (9). In piglets with inoculation pneumonia caused by P. aeruginosa with reduced susceptibility, multiple daily nebulizations of ceftazidime, a time-dependent antibiotic, provide greater lung deposition and more efficient bacterial killing than continuous intravenous administration (10).
Decreased susceptibility to antibiotics is a major health problem worldwide, and treating infections with the lowest ecological impact on bacterial resistance is emerging as a critical issue. Therefore, antibiotic nebulization, which provides high lung tissue concentration, deserves to be evaluated in patients with VAP. The present phase II study was designed to assess the efficacy and safety of combined nebulized ceftazidime and amikacin for treating VAP caused by P. aeruginosa. Clinical and bacteriological cure of VAP after 8 days of antimicrobial therapy was the primary end point. Secondary end points included antibiotic-induced changes in lung aeration and lung inflammation as assessed by computed tomographic scan and per-treatment emergence of resistant strains. Some of the results of this study have been previously reported in the form of an abstract (11).
After informed consent was obtained from patients relatives, patients admitted to the multidisciplinary intensive care unit of La Pitié-Salpêtrière Hospital (Paris, France) were randomly assigned to the aerosol or intravenous group in a prospective phase II trial. Eligibility criteria were as follows: age greater than 18 years and VAP caused by P. aeruginosa. VAP was defined according to clinical, biological, radiological, and quantitative bacterial criteria (12). P. aeruginosa had to be present at concentrations equal to or greater than 104 cfu·ml−1 in bronchoalveolar lavage (BAL) or equal to or greater than 103 cfu·ml−1 in protected mini-BAL (13). Exclusion criteria were as follows: treatment for more than 24 hours with antibiotics active against P. aeruginosa, extrapulmonary infection, expected extubation within 3 days, severe immunosuppression, allergy to penicillins or aminoglycosides, P. aeruginosa resistant to ceftazidime and/or amikacin, and PaO2/FIO2 (fraction of inspired oxygen) equal to or less than 100 mm Hg.
As previously recommended (7, 9, 10, 14), aerosol dose was determined as intravenous dose plus extrapulmonary deposition to deliver comparable amounts of ceftazidime and amikacin to the trachea and pulmonary artery. In 17 patients, the nebulization chamber and inspiratory and expiratory circuits were rinsed to assess extrapulmonary deposition (15). In the aerosol group, patients received eight aerosol administrations per day of ceftazidime (15 mg·kg−1; total, 120 mg·kg−1·d−1) for 8 days and a single daily aerosol administration of amikacin (25 mg·kg−1) for 3 days. A weaning test was authorized after 3 days of full treatment. If patients in the aerosol group were extubated before Day 8, ceftazidime was continued intravenously. In the intravenous group, patients received a bolus of ceftazidime (30 mg·kg−1 over 30 min) followed by a continuous infusion of 90 mg·kg−1·day−1 over 8 days, and a daily amikacin bolus of 15 mg·kg−1·day−1 over a 30-minute period for 3 days. Patients infected with P. aeruginosa intermediate in susceptibility to ceftazidime and/or amikacin were treated in the aerosol group with nebulized ceftazidime and amikacin and in the intravenous group with ciprofloxacin.
The protocol is summarized in Figure 1. Computed tomography (CT) of the whole lung was performed before initiation and after completion of antimicrobial therapy. On Days 3 and 4, amikacin plasma concentrations were measured by fluorescence polarization immunoassay and ceftazidime plasma concentrations were determined by high-performance liquid chromatography. On Day 9, response to antibiotic treatment was classified by nonblinded investigators as belonging in one of four categories: (1) “Cure” of VAP, defined as the association of reduction of clinical and biological signs of infection, decrease in modified Clinical Pulmonary Infection Score (CPIS) below 6, significant lung CT reaeration, and lower respiratory tract specimens either sterile or with nonsignificant concentrations of P. aeruginosa; (2) persisting VAP, defined as lack of improvement of clinical and biological signs, CPIS greater than 6, absence of CT lung reaeration, with significant concentrations of P. aeruginosa persisting in lower respiratory tract specimens; (3) recurrence of P. aeruginosa VAP, defined as initial cure after 8 days of antimicrobial therapy followed by posttreatment relapse of P. aeruginosa VAP; or (4) superinfection, defined as initial cure after 8 days of antimicrobial therapy followed by posttreatment relapse of VAP caused by pathogens other than P. aeruginosa.
Figure 1. Summary of the protocol. Aerosol = patients treated with nebulized ceftazidime and amikacin; BAL = bronchoalveolar lavage; CT = computed tomography; Intravenous = patients treated with intravenous ceftazidime and amikacin or ciprofloxacin; StrainI = Pseudomonas aeruginosa intermediate to ceftazidime (4 mg·L−1 < minimal inhibitory concentration ≤ 32 mg·L−1) and/or amikacin (8 mg·L−1 < minimal inhibitory concentration ≤ 16 mg·L−1).
[More] [Minimize]Nebulization was performed with vibrating plate nebulizers, using specific ventilator settings (see the online supplement). To standardize and optimize the nebulization procedure, a checklist form was completed by the nurse in charge of the patient (Figure 2). All adverse events were assessed for severity and for relationship to study treatment.
Figure 2. Checklist form filled out by the nurse before and after each aerosol administration. Ventilator settings fixed for the nebulization period were as follows: volume-controlled mode using constant inspiratory flow; respiratory frequency, 12 breaths·minute−1; inspiratory/expiratory ratio, 50%; tidal volume, 8 ml·kg−1; and end-inspiratory pause, 20%. AMK = amikacin; Cefta = ceftazidime; FIO2 = fraction of inspired oxygen; I/E ratio = inspiratory/expiratory ratio; RR = respiratory rate; TV = tidal volume.
[More] [Minimize]Contiguous axial 5-mm-thick CT sections of the whole lung were acquired at end-expiration on Days 0 and 9 (16). Volumes of gas and tissue and total lung volumes were computed (16, 17).
Antibiotic-induced lung reaeration after the 8-day treatment was measured as the increase in gas volume in lung regions characterized by multiple and disseminated foci of pneumonia and in lung areas of confluent bronchopneumonia (see Figure 3 and the online supplement) (18).
Figure 3. Computed tomographic assessment of lung reaeration in a patient treated by nebulization of ceftazidime and amikacin. Image 1 shows a computed tomographic (CT) section on Day 0 (before antibiotic administration) at the carina level, with lung regions characterized by multiple and disseminated nonconfluent foci of pneumonia (short arrows) and lung regions characterized by confluent pneumonia (long arrow). Image 2 shows a color-encoding analysis applied to the delineated right lung parenchyma. Normally aerated lung parenchyma is dark gray; interstitial pneumonia and/or edema is light gray; and foci of pneumonia, either disseminated or confluent, are red. Image 3 shows the manual delineation of lung regions characterized by multiple and disseminated nonconfluent foci of pneumonia and those characterized by confluent pneumonia (continuous and dashed lines, respectively). Image 4 shows the corresponding CT section (according to pulmonary vessels, bronchi, and mediastinal structures) on Day 9, after nebulization of ceftazidime and amikacin for 8 days. Image 5 shows the color-encoding analysis applied to the delineated right lung parenchyma. Image 6 shows the transposition of the delineation of both regions of interest performed on Day 0, on the CT section obtained on Day 9. By referring to anatomical landmarks such as pulmonary vessels, fissures, and segmental bronchi, the limit between the region characterized by multiple and disseminated foci of pneumonia and the region characterized by confluent pneumonia was manually redrawn on the CT section obtained on Day 9 according to the previous delineation performed on Day 0. Antibiotic-induced lung reaeration after the 8-day treatment was measured separately in lung regions characterized by multiple and disseminated nonconfluent foci of pneumonia and in lung areas of confluent pneumonia. It was defined as the increase in gas volume in each lung region of interest after the 8-day treatment.
[More] [Minimize]Data are expressed as means ± SD or as median and 25–75% interquartile range according to data distribution. Quantitative data were compared between groups by bilateral unpaired Student t test or Mann-Whitney rank-sum test. Changes in clinical signs and CT parameters were compared by two-way analysis of variance. The statistical significance level was fixed at 0.05.
Over a 36-month period, 79 patients with VAP caused by P. aeruginosa were screened for inclusion. Thirty-three patients were initially excluded for various reasons: 10 had received antibiotics active against P. aeruginosa for more than 24 hours, 13 had positive blood cultures, 6 were expected to be extubated within 3 days, 2 had PaO2/FIO2 ratios less than 100, and 2 had P. aeruginosa resistant to ceftazidime or amikacin. Ultimately, 46 patients were enrolled in the study. Twenty-four patients were randomly assigned to the aerosol group and 22 to the intravenous group (Figure 1). Six patients were secondarily excluded from the study within 1 day of treatment: 3 patients for bacteremia (2 in the aerosol group and 1 in the intravenous group), 1 patient in the aerosol group for severe hypoxemia related to rapid progression of lung injury leading to severe acute respiratory distress syndrome within 12 hours of inclusion (PaO2/FIO2 ratio, 75), and 2 patients for harboring a P. aeruginosa strain resistant to ceftazidime (1 patient in the aerosol group and 1 in the intravenous group), leaving 20 patients in each group. As shown in Table 1, clinical characteristics of the patients at baseline were not significantly different between groups.
| Aerosol (n = 20) | Intravenous (n = 20) | P Value | |
| Age (yr), mean ± SD | 58 ± 15 | 60 ± 17 | 0.71 |
| Male, n (%) | 15 (75) | 18 (90) | 0.41 |
| SAPS II, mean ± SD | 33 ± 13 | 30 ± 10 | 0.47 |
| SOFA, median (IQR) | 3.5 (2.5–7.5) | 3.0 (2.5–5.0) | 0.55 |
| CPIS, median (IQR) | 8 (7–8) | 9 (8–9) | 0.01 |
| COPD, n (%) | 3 (15) | 4 (20) | 1.00 |
| Circulatory shock, n (%) | 5 (25) | 2 (10) | 0.41 |
| Admission category, n (%) | 0.58 | ||
| Trauma | 7 (35) | 8 (40) | |
| Surgical | 12 (60) | 10 (50) | |
| Medical | 1 (5) | 2 (10) | |
| Body temperature, mean ± SD | 38.2 ± 0.6 | 38.5 ± 0.5 | 0.12 |
| Leukocyte count (cells/mm3), mean ± SD | 12,470 ± 5,582 | 13,205 ± 5,116 | 0.67 |
| PaO2/FIO2, mean ± SD | 266 ± 79 | 250 ± 66 | 0.49 |
In the intravenous group, all patients received the 8-day continuous infusion of ceftazidime, 17 received the 3-day amikacin administration, and 3 received a 3-day ciprofloxacin administration. In the aerosol group, all patients received the 3-day nebulization of amikacin whereas only nine patients received the 8-day nebulization of ceftazidime. Eleven patients of the aerosol group were extubated during the treatment period and 3 were reintubated within 48 hours. They received nebulized ceftazidime for 4.9 ± 1.2 days and intravenous ceftazidime for 2.9 ± 1.5 days. Four patients were initially infected with P. aeruginosa strains intermediate in susceptibility to ceftazidime and/or amikacin.
Of the initial amount of ceftazidime inserted into the nebulizer, 5 ± 3% was retained in the nebulizer chamber, 24 ± 10% was retained in the inspiratory limb of the respiratory circuit, and 8 ± 8% was retained in the expiratory filter. The total extrapulmonary deposition was 37 ± 11%. The resulting fraction of ceftazidime reaching the respiratory tract was 63% of the initial dose placed in the nebulizer chamber (120 mg·kg−1), representing a daily dose of 76 mg·kg−1 delivered to the respiratory tract.
Of the initial amount of amikacin inserted into the nebulizer, 5 ± 5% was retained in the nebulizer chamber, 25 ± 12% was retained in the inspiratory limb of the respiratory circuit, and 7 ± 3% was retained in the expiratory filter. The total extrapulmonary deposition was 37 ± 13%. The resulting fraction of amikacin reaching the respiratory tract was 63% of the initial dose placed in the nebulizer chamber (25 mg·kg−1), representing a daily dose 15.7 mg·kg−1 delivered to the respiratory tract.
At the end of the treatment (Day 9), cure of VAP was obtained in 70% of patients in the aerosol group and in 55% of patients in the intravenous group (P = 0.33). Treatment failure with persisting VAP caused by P. aeruginosa requiring continuation or restart of adequate antibiotics was observed in three patients in the aerosol group and in six patients in the intravenous group. As shown in Table 2, recurrence of VAP caused by P. aeruginosa or other microorganisms, length of stay, and duration of mechanical ventilation were not significantly different between groups.
| Aerosol (n = 20) | Intravenous (n = 20) | P Value | |
| Cure of P. aeruginosa VAP on Day 9, n (%) | 14 (70) | 11 (55) | 0.33 |
| Day 9: Positive BAL ≥ 104 cfu·ml−1 or mini-BAL ≥ 103 cfu·ml−1, n | 3 | 6 | |
| Persisting P. aeruginosa VAP on Day 9, n (%) | 3 (15) | 6 (30) | 0.26 |
| VAP caused by superinfection on Day 9, n (%) | 3 (15) | 3 (15) | NS |
| Recurrence of P. aeruginosa VAP, n | 3 | 1 | NS |
| Recurrence of VAP caused by superinfection, n | 2 | 0 | NS |
| Duration of MV, median (IQR) | 29 (22–38) | 18 (13–31) | 0.13 |
| Duration of MV after inclusion, median (IQR) | 14 (7–22) | 8 (6–12) | 0.18 |
| Length of stay in ICU, median (IQR) | 38 (29–55) | 29 (18–44) | 0.08 |
| Length of stay in ICU after inclusion, median (IQR) | 24 (18–48) | 16 (11–23) | 0.08 |
| Mortality on Day 28, n (%) | 2 (10) | 1 (5) | 0.55 |
Patients treated with nebulized ceftazidime and amikacin had rapid and early reduction of bacterial growth: bacterial cultures of BAL and protected mini-BAL were negative in 16 of 17 patients on Day 3 and in all patients on Day 5 (Table 3). P. aeruginosa reappeared in BAL and protected mini-BAL in two patients on Day 7 and in five patients on Day 9. On Day 9, two patients, considered to be successfully treated, had positive BAL with bacterial concentrations of 102 cfu·ml−1; three patients, considered as unsuccessfully treated, had positive mini-BAL equal to or greater than 103 cfu·ml−1. Isolated strains on Day 9 were all susceptible to ceftazidime and amikacin. In four patients initially infected with P. aeruginosa intermediate in susceptibility to ceftazidime and/or amikacin, these strains were successfully eradicated by nebulization. Pneumonia persisted in three patients, all infected with susceptible P. aeruginosa.
| Baseline | Day 3 | Day 5 | Day 7 | Day 9 | |
| Aerosol Group | |||||
| BAL, n | 20 | 17 | 16 | 12 | 12 |
| BAL P. aeruginosa + P. aeruginosa susceptibility, n | 20 | 1 | 0 | 2 | 5* |
| CAZ–AMK | |||||
| S–S | 16 | 1 | 2 | 5 | |
| S–I† | 1 | ||||
| I‡–S | 2 | ||||
| I§–I† | 1 | ||||
| Intravenous Group | |||||
| BAL, n | 20 | 16 | 15 | 10 | 11 |
| BAL P. aeruginosa + P. aeruginosa susceptibility, n | 20 | 8 | 8 | 5 | 6 |
| CAZ–AMK | |||||
| S–S | 17 | 6 | 5 | 1 | 3 |
| S–I | 3 | 2 | 1 | ||
| I–S | 1 | 2 | 1 | ||
| R–S | 2 | 1 | 1 | ||
| R–I | 1 | ||||
Patients treated with intravenous ceftazidime and amikacin had partial and delayed reduction of bacterial growth: bacterial cultures of BAL and protected mini-BAL were positive for P. aeruginosa in 40% of patients on Days 3 and 5, and in 25% of patients on Days 7 and 9 (Table 3). On Day 9, bacterial cultures of mini-BAL and BAL were, respectively, ≥ 103 cfu·ml−1 and ≥ 104 cfu·ml−1, in six patients with treatment failure. Interestingly, resistant strains were isolated in BAL and protected mini-BAL from Day 5. On Day 7, four of five isolated P. aeruginosa had become intermediate or resistant to either ceftazidime or amikacin. On Day 9, pneumonia persisted in six patients, three of them being infected with P. aeruginosa intermediate or resistant to either ceftazidime and/or amikacin.
At baseline, aerosol and intravenous groups did not differ in terms of total gas volume (1,082 [805–1561] vs. 1,419 [1,216–1,737] ml; P = 0.17), gas volume in regions of confluent pneumonia (86 [54–161] vs. 64 [49–124] ml; P = 0.41), total tissue volume (1,025 ± 269 vs. 969 ± 242 ml; P = 0.54), and tissue volume in regions of confluent pneumonia (507 ± 214 vs. 423 ± 166 ml; P = 0.26).
In patients of both groups successfully treated by antibiotics, gas volume increased significantly in regions with nonconfluent foci of pneumonia and in regions of confluent pneumonia (Figure 4A). In the aerosol group, lung reaeration was observed not only in patients with VAP caused by susceptible P. aeruginosa (Figure 5) but also in patients with VAP caused by intermediate P. aeruginosa (Figure 6). Tissue volume remained unchanged in regions with nonconfluent foci of pneumonia and significantly decreased in regions of confluent bronchopneumonia (Figure 4B). These changes were similar in both groups.
Figure 4. Computed tomographic assessment of gas and tissue volumes in lung regions characterized by multiple and disseminated foci of pneumonia (left) and in lung areas of confluent pneumonia (right) on Days 0 and 9, in patients treated with intravenous (open circles) and nebulized (solid circles) ceftazidime and amikacin. (A and B) Gas and tissue volume changes in aerosol and intravenous group patients successfully treated by antimicrobial therapy. (C and D) Changes in gas and tissue volumes in aerosol and intravenous group patients in whom antimicrobial therapy was unsuccessful. IV = intravenous; NS = not significant.
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Figure 5. Computed tomographic assessment of lung reaeration resulting from 8-day nebulization of ceftazidime and amikacin in a 53-year-old patient with ventilator-associated pneumonia (VAP) caused by susceptible Pseudomonas aeruginosa. VAP developed in the postoperative period after the surgical repair of a major thoracoabdominal aneurysm. On the left, six computerized tomographic sections representative of both lungs and acquired before starting antibiotics are shown with the corresponding color-encoding system (normally aerated lung regions are dark gray; interstitial pneumonia and/or edema are light gray; and foci of pneumonia, either disseminated or confluent, are red). On the right, the same six computerized tomographic sections acquired after 8-day nebulization of ceftazidime and amikacin are shown. Nebulization of antibiotics induced a 1,000-ml lung reaeration, predominating in regions of confluent pneumonia.
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Figure 6. Computed tomographic assessment of lung reaeration resulting from 8-day nebulization of ceftazidime and amikacin in a 32-year- old patient with ventilator-associated pneumonia caused by Pseudomonas aeruginosa intermediate to ceftazidime (minimal inhibitory concentration of 12 mg·L−1) and susceptible to amikacin complicating severe multiple trauma. On the left, six computerized tomographic sections, representative of both lungs and acquired before starting antibiotics, are shown with the corresponding color-encoding system (normally aerated lung regions are dark gray; interstitial pneumonia and/or edema are light gray; foci of pneumonia, either disseminated or confluent, are red). On the right, the same six computerized tomographic sections acquired after 8-day nebulization of ceftazidime and amikacin are shown. Nebulization of antibiotics induced a 930-ml lung reaeration, both in regions of nonconfluent foci of pneumonia and in regions of confluent pneumonia.
[More] [Minimize]In patients in whom antimicrobial therapy failed, gas volume significantly decreased in regions with nonconfluent foci of pneumonia (Figure 4C, left) and remained unchanged in regions of confluent pneumonia (Figure 4C, right). These changes were similar in both groups.
Bronchospasm was not observed. Mean PaCO2 (39 ± 4 vs. 40 ± 7 mm Hg; P = 0.52) and median PaO2 (242 [194 – 256] vs. 240 [199 – 259] mm Hg; P = 0.35) were not different before and after nebulization. However, in three patients with an initial PaO2/FIO2 ratio less than 200, PaO2 decreased by 25% at the end of the nebulization period. One patient was excluded during the early phase of the study for severe hypoxemia related to nebulization-induced alveolar derecruitment.
Three adverse events related to obstruction of the expiratory filter were reported, among which one was considered a serious adverse event. Obstruction of the expiratory filter was detected as an increase in peak airway pressure in two patients and sudden cardiac arrest in one patient. Expiratory obstruction resolved after immediate replacement of the expiratory filter. After early cardiopulmonary resuscitation, the patient had full recovery and left the intensive care unit on Day 24.
As shown in Table 4, after 4 days of continuous intravenous administration of ceftazidime, trough concentrations were greater than eightfold the minimal inhibitory concentration (MIC) of susceptible strains. After 3 days of intravenous administration of amikacin, peak plasma concentrations were greater than fivefold the MIC of susceptible strains, whereas trough concentrations were less than 5 mg·L−1.
| Aerosol | Intravenous | P Value | |
| Ceftazidime | |||
| Daily dose, mg·kg−1 | 76* | 90 | |
| Cpeak, mg·L−1 | 12.1 ± 8.4 | ||
| Ctrough, mg·L−1 | 8.1 (6.0–12.4) | 32.2 ± 9 | <0.001 |
| Amikacin | |||
| Daily dose, mg·kg−1 | 15.7* | 15.0 | |
| Cpeak, mg·L−1 | 8.9 (5–11) | 45.1 (33–58) | <0.001 |
| Ctrough, mg·L−1 | 2.4 (1.7-5.9) | 3.3 (1.9–5.8) | 0.742 |
As shown in Table 4, after a 4-day nebulization of ceftazidime, peak and trough concentrations were significantly lower than after intravenous administration. After three daily nebulizations of amikacin, peak plasma concentrations were fivefold less than after intravenous administration, whereas trough concentrations were not different.
This clinical pilot phase II trial shows that nebulization and intravenous infusion of ceftazidime and amikacin have similar efficiency in terms of clinical and radiological cure of VAP caused by susceptible P. aeruginosa. Nebulization of ceftazidime and amikacin is also efficient to treat patients with VAP caused by intermediate P. aeruginosa. Interestingly, nebulization of ceftazidime and amikacin provides more rapid bacterial eradication from distal pulmonary samples than intravenous administration. Incidence of antimicrobial therapy failure and VAP recurrence was similar in both groups. In patients treated with aerosols, however, new P. aeruginosa growth or persistence was caused exclusively by susceptible strains, whereas in the intravenous group, 50% of P. aeruginosa strains isolated on Day 9 had become intermediate or resistant to one or both antibiotics. Confirming experimental studies, nebulization did not reduce trough amikacin concentrations, which are the main determinants of systemic toxicity (9). The technique of nebulization is quite demanding and requires standardized aerosol procedures to optimize distal lung deposition. It can be associated with obstruction of the expiratory filter and deterioration of arterial oxygenation. Such adverse effects are detected as an increase in peak airway pressure and a decrease in arterial oxygen saturation.
On the basis of promising experimental studies (9, 10), the present clinical pilot phase II study was designed to assess clinical efficiency and safety of combined nebulized ceftazidime and amikacin in P. aeruginosa VAP. Cure of VAP was observed in 70% of patients treated with nebulized ceftazidime and amikacin. Half of failures of antimicrobial therapy were caused by superinfection with other microorganisms and half by lack of eradication of P. aeruginosa. As a consequence, nebulization of ceftazidime and amikacin could eradicate 85% of strains of P. aeruginosa from the deep lung. This result is slightly superior to that obtained with intravenous antibiotics (70%). In addition, nebulization has two potential advantages over intravenous administration.
First, nebulization provides an efficient cure for VAP caused by P. aeruginosa intermediate in susceptibility to amikacin and/or ceftazidime. As unanimously admitted and experimentally demonstrated (19), such a result cannot be achieved by intravenous administration. As a consequence, patients of the intravenous group infected with P. aeruginosa intermediate in susceptibility to amikacin were treated with ciprofloxacin, a molecule well known to increase the risk of antibiotic resistance in intensive care units (20, 21). Further studies are required to confirm the superiority of nebulized antibiotics for treating VAP caused by pathogens with reduced susceptibility.
Second, persisting and recurrent infection was caused by P. aeruginosa remaining susceptible to amikacin and ceftazidime in all patients in the nebulized group and in half of the patients in the intravenous group. These findings are in accordance with a study showing that nebulized antibiotic combined with intravenous antibiotics decrease bacterial resistance in patients with ventilator-associated tracheobronchitis (22). In the present study, tissue concentrations far greater than mutant prevention concentrations (23, 24) likely reached infected lung regions after aerosol administrations, thereby avoiding the selection of resistant strains. In the intravenous group, ceftazidime plasma concentrations were eightfold higher than the MIC of susceptible P. aeruginosa. Trough concentrations of time-dependent antibiotics are close to lung interstitial tissue concentrations, the critical concentrations required for killing susceptible microorganisms. Therefore, the intravenous route was as efficient as nebulization for eradicating susceptible strains infecting the lung. Because ceftazidime trough concentrations were only one- to threefold higher than the MIC of intermediate strains of P. aeruginosa, it justifies a posteriori the replacement of ceftazidime and amikacin by ciprofloxacin (25).
It is widely accepted that the duration of antimicrobial therapy for VAP can be restricted to 8 days (12, 26). There is, however, some evidence suggesting that P. aeruginosa VAP should be treated for 2 weeks with a combination of appropriate antibiotics (27, 28). The longer duration of treatment is aimed at reducing the high incidence of P. aeruginosa VAP relapse, attributed to the presence of the type III secretion system, which interferes with neutrophil functions and impairs bactericidal activity–induced antibiotics (29). In the present study, the duration of treatment was fixed at 8 days with the hope that high antibiotic lung tissue deposition and rapid bactericidal activity at the site of infection (7, 9, 10, 14) would reduce the incidence of relapse and recurrence in the aerosol group. Unfortunately, these expected benefits were not observed, suggesting that either high antibiotic concentrations do not inhibit type III secretion system or that reservoirs of P. aeruginosa, such as in the oropharynx or on the endotracheal cuff (30), or in the biofilm (31) present on the internal walls of the endotracheal tube, were not affected by nebulized antibiotics (32).
With the small sample size of this pilot study, the power was insufficient to test a significant difference in cure rate between the study groups. A nonsignificant 15% absolute increase in cure of P. aeruginosa VAP was found on Day 9 in the nebulization versus the intravenous group. However, the power to detect a significant difference at an α risk of 0.05 was limited to 16%. An absolute difference of 41.5% would have been required to reach statistical significance at a β risk of 0.20. The positive trend in cure rates of P. aeruginosa VAP on Day 9 emphasizes the need for a further trial that is adequately powered.
The population study may not be entirely representative of the population of patients with VAP caused by P. aeruginosa because some selection criteria may have introduced a potential bias. As patients treated by antibiotics active against P. aeruginosa for more than 24 hours were excluded and identification of P. aeruginosa in a distal pulmonary sample was a prerequisite for inclusion, most included patients were initially treated with inadequate antibiotics. Therefore the selected population may have had increased morbidity and mortality related to inappropriate initial antibiotic therapy (33–35). In other words, a subpopulation of patients with more severe respiratory prognoses may have been studied.
P. aeruginosa eradication was more frequently observed in the aerosol group compared with the intravenous group. Such a result may have been overestimated by the fact that some patients were extubated before the end of antimicrobial treatment, a condition rendering it difficult to obtain distal pulmonary samples. This hypothesis seems unlikely, however, because the same proportion of patients was extubated in the intravenous group. A carryover effect, inhibiting bacterial growth in bronchoalveolar lavage and not indicating true bacterial killing, cannot be formally excluded.
Last but not least, 20% of patients with P. aeruginosa VAP had positive blood cultures and had to be excluded because nebulization of ceftazidime and amikacin does not provide enough plasma concentrations to efficiently treat extrapulmonary infections (Table 4).
Iterative daily aerosols of time-dependent antibiotics are required to ensure efficient bactericidal activity against P. aeruginosa (10). To decrease impaction of aerosol particles on ventilator circuits and to optimize distal lung deposition, specific ventilator settings are required. They are all aimed at reducing turbulence of inspiratory flow and frequently impose sedation to synchronize patients. To guarantee appropriate antibiotic administration, a checklist form was completed by the nurse in charge of the patient before and after each aerosol administration (Figure 2). Bronchospasm was not observed. Disconnection of the patient from the ventilator was repeated every 3 hours for ceftazidime nebulization. Even though aerosols were generally well tolerated in terms of arterial oxygenation, a 25% decrease in PaO2 at the end of aerosol administration was observed in three patients. One patient had to be excluded because of severe hypoxemia related to rapid progression of lung injury leading to severe acute respiratory distress syndrome. In this situation, disconnection from the ventilator required before each nebulization for changing the expiratory filter was considered a risky procedure. Three adverse events related to obstruction of the expiratory filter by aerosol particles were reported. One of them induced a brief cardiac arrest, emphasizing the need for close monitoring of airway pressure during nebulization. To prevent expiratory obstruction, a new expiratory filter should be inserted before each new nebulization. To detect arterial oxygenation impairment and progressive obstruction of the expiratory filter during the nebulization procedure, oxygen saturation and peak airway pressure alarms should be appropriately set before commencing, and the checklist form (Figure 2) should be completed after aerosol administration to ensure that the expiratory filter is removed.
In conclusion, nebulization and intravenous infusion of ceftazidime and amikacin provide similar efficiency in terms of clinical cure of VAP caused by susceptible P. aeruginosa. Nebulization provides clinical cure of VAP caused by P. aeruginosa with reduced susceptibility and may prevent the per-treatment emergence of resistant strains. It does not reduce the incidence of VAP recurrence. These benefits are obtained only if conditions of nebulization are optimized and adverse events such as obstruction of the expiratory filter are detected early enough. A large multicenter randomized trial is required to determine whether these potential benefits outweigh the risks of serious adverse events in patients with P. aeruginosa ventilator–associated pneumonia.
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* A complete list of members may be found before the beginning of the References.
Supported by a research scholarship from the Department of Emergency Medicine of the Second Affiliated Hospital of Hangzhou, China (J.Y.), and a research scholarship from the Association pour la Recherche Clinique et Expérimentale en Anesthésie-Réanimation (ARCEAR) of the Department of Anesthesiology and Critical Care Medicine, La Pitié-Salpêtrière Hospital, Paris, France (Z.L.). Vibrating plate nebulizers were provided by Aerogen Nektar Corporation (Gateway, Ireland). Other support was provided from institutional and/or departmental sources.
Authors' contributions: Q.L. performed the study and drafted the manuscript. J.Y., Z.L., and C.G. participated in the study and study analysis. G.A. performed measurement of plasma concentrations of antibiotics and participated in the interpretation of the results. J.J.R. initiated the study, participated in the design and conception of the study, and helped to improve the draft. Members of the Nebulized Antibiotics Study Group participated directly to the study by contributing to include patients and/or participating in the redaction of the manuscript.
This article has an online supplement, which is available from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201011-1894OC on April 7, 2011
Author disclosures
Members of the Nebulized Antibiotic Study Group: Charlotte Arbelot, Hélène Brisson, Belaïd Bouhemad, Alexis Soummer, Fabio Ferrari, Antoine Monsel, Liliane Bodin (Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care Medicine, La Pitié-Salpêtriére Hospital, Assistance-Publique-Hôpitaux-de-Paris, UPMC Univ Paris 06, France); Rubin Luo, Mao Zhang (Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China); Alexandra Aubry, Florence Brossier, Jèrôme Robert, Vincent Jarlier (Department of Bacteriology, La Pitié-Salpêtriére Hospital, UPMC Univ Paris 06); Philippe Lechat, Christian Funck-Brentan (Department of Pharmacology, La Pitié-Salpêtriére Hospital, UPMC Univ Paris 06).
