Nebulized Versus IV Amikacin as Adjunctive Antibiotic for Hospital and Ventilator-Acquired Pneumonia Postcardiac Surgeries: A Randomized Controlled Trial

Miguel Zayas, Mercer University College of Pharmacy

Pneumonia is the most common infection in mechanically ventilated patients with risk of infection being associated with duration of mechanical ventilation. [1] The 2016 Infectious Disease Society of America (IDSA) guideline on healthcare and ventilator associated pneumonia (HAP and VAP) currently recommends a beta-lactam antibiotic along with either an intravenous (IV) fluoroquinolone or IV aminoglycoside. The use of inhaled aminoglycosides is recommended as a treatment of last resort if patients are not responsive to IV antibiotics alone (weak recommendation, very low-quality of evidence). [2] However, recently, nebulized antibiotics use as an adjunctive therapy has been increasing due to the decreased risk of nephrotoxicity and greater localization at the intended site of action when treating suspected multi-drug resistant gram-negative bacilli (MDR-GNB). [3,4]

 

Nebulized Versus IV Amikacin as Adjunctive Antibiotic for Hospital and Ventilator-Acquired Pneumonia Postcardiac Surgeries: A Randomized Controlled Trial
Design Prospective, randomized, controlled study; N= 133
Objective To evaluate the efficacy and nephrotoxicity of nebulized versus IV amikacin in post-cardiothoracic surgery patients with nosocomial pneumonia caused by multi-drug resistant gram-negative bacilli (MDR-GNB)
Study Groups ·         IV amikacin 20 mg/kg once daily diluted in 100 mL 0.9% NaCl over 1 hour + IV piperacillin/tazobactam

·         amikacin 400 mg diluted in 10 mL 0.9% NaCl twice daily via nebulizer + IV piperacillin/tazobactam

Methods Inclusion criteria: adults from 21-65 years old, glasgow coma score (GCS) score between 4 and 15, positive culture confirming a MDR-GNB susceptible to amikacin that requires a dual antibiotic therapy, and clinical suspicion of HAP or VAP

 

Exclusion criteria: patients with a recorded allergy due to the sulfite component in amikacin, multi-organ dysfunction, psychiatric illness, intolerance to nebulized amikacin, pregnancy, current lactation, brain death, or baseline CrCl < 30 mL/min.

 

Sputum samples were collected by spitting from nonventilated patients, while patients who had endotracheal intubation had aspirate collected. Bacteria was identified using “Vitek” device which performed antimicrobial testing within 48 hours. Patients were then randomized into the two groups. All patients received a low dose of furosemide and captopril as part of post-operative care for cardiac surgery. A nebulized bronchodilator, ipratropium 500 mcg four times daily, was administered prior to nebulized amikacin. IV piperacillin-tazobactam was administered empirically in both arms of the study for gram negative coverage. De-escalation occurred by discontinuing amikacin once patients showed clinical improvement and discontinuing piperacillin-tazobactam once clinical cure was noted. Duration of therapy depended on individual patient responses.

Duration August 2014 to August 2015
Primary Outcome Measure Clinical cure on day 7 of amikacin initiation defined as normalized body temperature, T cell count < 10,000 cells/mL, absence of purulent secretions, and improvement of radiological findings. Patients on VAP were also expected to have PaO2/FiO2
Baseline Characteristics
Parameter Nebulizer Group (n = 86) IV Group (n = 47) p
Age (years) 48 (44-57) 51 (45-58) 0.731
Body Weight (kg) 80 (73-97) 90 (80-90) 0.221
Gender n(%male) 45 (52.3) 26 (55.3) 0.741
European System for Cardiac Operative Risk Evaluation score II 2.28 (1.4-3.8) 2.24 (1.6-2.7) 0.930
Type of operation (CABG), n(%) 31 (36) 22 (25.5) 0.442
Patients with CrCl <60mL/min, n (%) 16 (18.6) 7 (14.89) 0.588
Baseline serum SCr (mg/dL) 1.1 (0.7-1.2) 1 (0.8-1.1) 0.111
Baseline CrCl (mL/min) 91 (80-124) 97 (88-113) 0.053
Body temperature (ºC) 38 (38-93) 38.2 (38-39) 0.409
Patients with elevated body temp. (≥ 38 ºC), n(%) 74 (86) 41 (89.1) 0.84
Patients with elevated leukocyte count (>11 x 109/L), n (%) 84 (97.67) 46 (97.8) 0.941
Patients diagnosed with VAP, n (%) 48 (55.83) 31 (66) 0.255
Results
Parameters Nebulizer Group (n= 86) IV Group (n=47) p-value
Clinical cure, n (%) 79 (91.8) 33 (70.2) 0.002
Mortality, n (%) 20 (23.3) 12 (25.5) 0.544
Mortality excluding patients with nonrelevant complications 14 (17.9) 7 (17.07) 0.905
Length of hospital stay (d) 25 (16-31) 26 (17-48) 0.207
Length of ICU stay 6 (3-12) 9 (5-13) 0.147
Days to reach clinical cure 10 (7-11) 11 (5-12) 0.001
Duration of Amikacin treatment 7 (5-9) 8 (7-10) 0.022
Duration of MV (d) 3 (2-6) 7 (3-11) 0.035
Resolution of X-ray, n(%) 77 (89) 32 (68) 0.03
Patients with acute kidney injury, n(%) 6 (6.97) 9 (10.4) 0.0232
Increase in serum creatinine (mg/dL) 0.1 (0-0.2) 0.4 (0.2-0.6) < 0.001
Number of patients with sepsis, n(%) 21 (24) 9 (19) 0.0524
Adverse Events Common Adverse Events: Not disclosed
Serious Adverse Events:

Nebulized amikacin: need for hemodialysis (n= 0), bronchospasm (n= 2)

IV amikacin: need for hemodialysis (n= 3)

Percentage that Discontinued due to Adverse Events: Not disclosed
Study Author Conclusions Inhaled amikacin showed better efficacy and lower nephrotoxicity compared to the IV regimen when either were combined with piperacillin-tazobactam in treating suspected MDR-GNB nosocomial pneumonia after cardiac surgery.

 

The results show that amikacin is an effective treatment for MDR-GNB with lower risks of adverse events that are generally associated with IV aminoglycosides. The dose used in this trial was derived from a study of a novel investigational drug device, which also found a positive outcome using the same dose. [5] Although the investigators did not use the same device, based on the positive outcomes, it may be suggested that nebulizers may also be able to deliver adequate amount of drug to the site of infection. However, there is no objective comparison or assessment of drug concentration at the site of infection to definitively support the statement. Another difference is that the authors used a combination therapy; therefore, it cannot be certain whether the outcomes are solely attributable to amikacin. Nevertheless, both studies of aerosolized amikacin show that localized drug delivery may be an effective treatment strategy for HAP and VAP as it is associated with positive outcomes while using lower doses than IV treatment (400 mg/day vs. 15-20 mg/kg/day). [6] Another consideration is that sputum culture was used instead of bronchoalveolar lavage, which would provide more accurate diagnosis. However, due to its invasive nature, use of bronchoalveolar lavage may have been limited for this study. The authors did not report MIC of the organisms, which may limit the applicability of the results in institutions with higher rates of resistance. The choice of amikacin over other aminoglycosides (i.e. tobramycin and gentamicin) was appropriate as amikacin is a synthetic aminoglycoside and may still be effective in organisms that are resistant to other aminoglycosides. [7] Moreover, in this group of patients, sensitivity to amikacin was higher compared to gentamicin for all organisms, which further supports use of amikacin. Overall, despite the limitations, the results suggest that is may be reasonable to consider inhaled amikacin over IV amikacin in HAP or VAP caused by MDR-GNB.

 

References

[1] Hassan NA, Awdallah FF, Abbassi MM, Sabry NA. Nebulized versus IV amikacin as adjunctive antibiotic for hospital and ventilator-acquired pneumonia postcardiac surgeries: a randomized controlled trial. Crit Care Med. 2017

[2] Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016

[3] Palmer LB: Aerosolized antibiotics in the intensive care unit. Clin Chest Med 2011; 32:559-574.

[4] Bruce MA, Shirley V, Tammy A, et al: A randomized double-blind placebo-controlled dose-escalation phase 1 study of aerosolized amikacin and fosfomycin delivered via the PARI investigational eFlow® Inline nebulizer system in mechanically ventilated patients. J Aerosol Med Pulm Drug Deliv 2014; 27:441-448

[5] Niederman MS, Chastre J, Corkery K, Fink JB, Luyt CE, García MS. BAY41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia. Intensive Care Med. 2012;38(2):263-71.

[6] Florescu DF, Mindru C, Keck MA, Qiu F, Kalil AC. Colistin, an old drug in a new territory, solid organ transplantation. Transplant Proc. 2016;48(1):152-7.

[7] Gad GF, Mohamed HA, Ashour HM. Aminoglycoside resistance rates, phenotypes, and mechanisms of gram-negative bacteria from infected patients in upper Egypt. PLoS ONE. 2011;6(2):e17224.

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