INHALATIONAL ANTIBIOTICS IN ICU

Ubaidur Rahaman Senior Resident Dept of CCM, SGPGIMS, Lucknow,India

INHALATIONAL ANTIBIOTICS IN ICU

Respiratory tract as a conduit for therapeutic drug delivery

not a new concept

inhaled aerosols, smoke, and steam for pleasure, and spiritual enlightment.

INHALATIONAL ANTIBIOTICS IN ICU

WHY NEW ROUTE

COLONIZATION
OROPHARHYNGEAL

PROPHYLAXIS

TRACHEOBRONCHEAL

Tracheobronchitis
TREATMENT

Pneumonea

INHALATIONAL ANTIBIOTICS IN ICU

WHY NEW ROUTE Systemic Antibiotics

n Higher therapeutic dose dose delivery to target organ

higher Vd in critically ill patient

ADVERSE EFFECTS

Inhaled therapy
n Higher dose delivery to distal airways and lung parenchyma- lower therapeutic

dose n Lower risk of systemic side effects

INHALATIONAL ANTIBIOTICS IN ICU

IS IT EFFECTIVE
Lung distribution and pharmacokinetics of nebulized tobramycin
-Le Conte P, Am rev resp dis1993, 147:1279-82 147:1279-

Mean lung tissue conc.

5.5ug/ml

after 4 hours ;

3-61ug/ml

after 12 hours

Concentration of gentamycin in bronchial secretion after intramuscular and endobronchial administration- Klastersky J, J clin pharmacol, 1975, 15, 518-24 Gentamycin 2mg/kg: I.M. route Endobronchial route concentration achievedendobronchial secretion <2ug/ml >400ug/ml serum >6ug/ml <1ug/ml

To prevent toxicity DESIRED TROUGH SERUM CONC- < 1-2 ug/ml CONC- 1- ug/ml ( Goodmann and Gilmans the pharmacological basis of therapeutics 11th edi-2006) Gilman edi-

Inhaled amikacin achieves high epithelial lining fluid concentration in Gram neg pneumonea in intubated an mechanically ventilated patients.
Luyt CE, Jacob A, Am J Respir Crit Care Med 2007; 175:A 328

INHALATIONAL ANTIBIOTICS IN ICU

IS IT EFFECTIVE
Aerosolized antibiotic in mechanically ventilated patients: delivery and response.
Lucy B. Palmer, Gerald C. Smaldone, crit care med; 1998; 26:1:31-39 Smaldone, 26:1:31-

Aerosolized amikacin and gentamycin for 14-21 days in 9 cycles in mechanically venilated stable patients colonized with G neg organism producing purulent secrection

dose delivered to lung was 21.9% of neb charge sputum conc- peak- 1005-5839 ug/ml, trough- 234-520 ug/ml serum conc- undetectable in all (except one who was in renal failure-8.7 ug/ml of amikacin)
DESIRED TROUGH CONC OF AMIKANCIN- < 5-10 ug/ ml

weekly culture revealed eradication of pseudomonas, serratia mersescence, enterobactor aerogenes

EFFICACY IN CRITICALLY ILL PATIENT TO BE DETERMINED

INHALATIONAL ANTIBIOTICS IN ICU

PAST
n Documented efficacy in cystic fibrosis

n Data are scarce in critically ill patients on mechanical

ventilation
since 1950 - earlier trial ended in increased incidence of infection and adverse effects ( Aerosol Polymyxin and Pneumonia in Seriously Ill Patients T. W. Feeley, G. C. du Moulin,,
N Engl J Med 1975; 293:471-475)

INHALATIONAL ANTIBIOTICS IN ICU

PREVENTION OF COLONIZATION AND NOSOCOMIAL PNEUMONEA

of antibiotics via the respiratory tract for the prevention of ICU-acquired pneumonia: a meta-analysis of comparative trials. Crit Care 2006; 10:R123.
Falagas ME, Siempos II, Bliziotis IA, Michalopoulos: Administration

1950 2005:Meta-analysis of 5 RCTs (414 pts)

ICU-acquired pneumonia was statistically less common in the cohorts receiving aerosolized antibiotic prophylaxis. No difference in mortality Could not evaluate effect on resistance of bacteria

INHALATIONAL ANTIBIOTICS IN ICU

PREVENTION OF NOSOCOMIAL PNEUMONEA

Characteristics of comperative trial included in meta analysis
Reference Wood et al Rouby et al Rathgerber et al Lode et al Vogel et al Klick et al Klatersky et al Greenfield et al Year Pt. no.
2002

Study drug/ dose Ceftazidime 250 mg q12h Colistin 0.2 mu q3h Tobramycin 80 mg q6h Gentamycin 40 mg q6h Gentamycin 40 mg q6h Polymyxin B 2.5 mg/kg bw/d in 6 divided doses Gentamycin 80 mg q8h Polymyxin B 2.5 mg/kg bw/d in 6 divided doses

40 598 69 162 40 692 85 58

1994 1993 1992 1981 1975 1974 1973

INHALATIONAL ANTIBIOTICS IN ICU INHALATIONAL ANTIBIOTICS IN ICU

TREATMENT OF TRACHEOBRONCHITIS
Palmer LB, Smaldone GC, Chen JJ, et al.

Aerosolized antibiotics and ventilator-associated tracheobronchitis in the ICU

Crit Care Med 2008; 36:20082013.

Based on Gram stain of the tracheal aspirate, 43 patients received aerosolized vancomycin or gentamycin for 14 days versus placebo. Iv antibiotics prescribed on physician discretion

reduced clinical signs of respiratory infection, pulmonary infection score, progression to VAP, Reduced bacterial resistance, reduced use of systemic antibiotics, and earlier discontinuation of mechanical ventilation.

No difference in WBC before or after therapy No difference in mortality

INHALATIONAL ANTIBIOTICS IN ICU INHALATIONAL ANTIBIOTICS IN ICU

TREATMENT OF TRACHEOBRONCHITIS
Nseir S, Favory R, et. Antimicrobial

treatment for ventilator associated tracheobronchitis A randomised controll multicentre study. Crit Care 2008;12:R62

Significant decrease in progression to VAP Earlier discontinuation of mechanical ventilation Reduced mortality

Serial ETA monitoring to diagnose VAP Randomised to receive aerosolized therapy vs no therapy

INHALATIONAL ANTIBIOTICS IN ICU

INHALATIONAL ANTIBIOTICS IN ICU

TREATMENT OF NOSOCOMIAL PNEUMONEA

Administration of antibiotics via the respiratory tract for the treatment of patients with nosocomial pneumonia: a meta-analysis. J Antimicrob Chemother 2007; 60:12161226.
Ioannidou E, Siempos II, Falagas ME.

META ANYLYSIS OF 5 TRIALS Statistically higher success rate for the treatment of nosocomial pneumonia if receiving inhaled or endotracheally instilled antibiotics in the 176 patients.

No difference was demonstrated for mortality, emergence of resistance, or adverse event.

INHALATIONAL ANTIBIOTICS IN ICU

INHALATIONAL ANTIBIOTICS IN ICU

MONOTHERAPY OF NOSOCOMIAL PNEUMONEA

Falgas ME, Agrafiotis M, Athanassa Z, et al

Administration of antibiotic through respiratory tract as monotherapy for pneumonea

Exper Rev Antiinf Ther 2008;6:447-452

This therapy might be considered when systemic access is not available, refused by the patient or concern regarding bioavailability to lung or systemic toxicity

TREATING PATIENT WITH VAP WITH AEROSOLIZED ANTIBIOTIC ALONE IS PREMATURE

INHALATIONAL ANTIBIOTICS IN ICU

INHALATIONAL ANTIBIOTICS IN ICU

RECOMMENDATION FOR PREVENTION OF NOSOCOMIAL PNEUMONEA Recent evidence base reviews have interpreted supporting data as week Universally recommended against routinely using for VAP prophylaxix untill stronger data are available Role of inhaled anibacterial in hospital aquired and ventilator associated pneumonea . Lesho E. Expert Rev Anti Infect Ther 2005;3(3):445-451 Despite optimized delivery systemsinhaled antibiotics can still not be recommended for preventing VAP Aerosolized antibiotics: a critical appraisal of their use.
Hagerman JK, Hancock KE, Klepser ME. Expert Opin Drug Deliv 2006;3(1)71-78

There are limited data available to support the routine use of this modality

INHALATIONAL ANTIBIOTICS IN ICU

RECOMMENDATION FOR TREATMENT OF NOSOCOMIAL PNEUMONEA

MULTIPLE CONSENSUS GROUP RECOMMEND AGAINST USING IN ESTABLISHED VAP ESPECIALLY AS MONOTHERAPY ( Neil R MacIntyre, Bruce K Rubin MEngr, Should Aerosolized antibiotic be administered to prevent or treat VAP in patient who do not have cystic fibrosis? Respir Care, April 2007;52;4:416-20 )

CAN BE RECOMMENDED TO TREAT MDR VAP COLISTIN AND AGS

(C.E. Luyt, Alain Combes, Ania Nieszkowska, JL Trouillet,

Aerosolized antibiotics to treat VAP.

Curr Opin infect dis ;2009;22:154-158)

Legal concern-

NO RECOMMENDATION ABOUT ANTIBIOTIC INDICATION ,SELECTION, DOSE, FREQUENCY, DURATION

airway as a route of Antiobiotic delivery not approved by USFDA

(EVEN FOR TOBRAMYCIN FOR WHICH SPECIFIC PREPARATION TOBI IS AVAILABLE)

INHALATIONAL ANTIBIOTICS IN INHALATIONAL ANTIBIOTICS IN ICU ICU

IT IS VERY POSSIBLE THAT AEROSOLIZED ANTIBIOTIC MAY BECOME A MAINSTAY IN PREVENTING VAP IN FUTURE
Neil R MacIntyre, Bruce K Rubin MEngr, Should

Aerosolized antibiotic be administered to prevent or treat VAP in patient who do not have cysic fibrosis? Respir Care, April 2007;52;4:416-20 )

INHALATIONAL ANTIBIOTICS IN ICU ICU INHALATIONAL ANTIBIOTICS IN

PROBLEMS
PATIENT RELATED DEVICE RELATED DRUG RELATED

DRUG DELIVERY
VENTILATOR RELATED CIRCUIT RELATED

BRONCHOSPSM
EMERGENCE OF

Pretreatment with albuterol 2.5 mg

RESISTANCE

SYSTEMIC TOXICITY

AND

INTRODUCTION OF NEW INFECTION

INHALATIONAL ANTIBIOTICS IN ICU

INHALATIONAL ANTIBIOTICS IN ICU

PROBLEMS- DRUG DELIVERY

PATIENT RELATED:
Airway obstruction Dynamic hyperinflation PVA

DRUG RELATED: VENTILATOR RELATED:

Dose Particle size- 1-5 micron Volume- 4-5 ml( neb charge)

MODE- spontaneous, volume control Vt- higher >500, small Vd RR- lower Ti- longer flow waveform- square waveform better than descending ramp triggering- flow triggering loss of drug

CIRCUIT RELATED:

ETT Inhaled gas humidity Inhaled gas density/ viscocity

Tubing acts as spacer device and increases respirable fraction

Type of nebulizer- Jet/ ultrasonic

DEVICE RELATED:

Flow 6-8 lt Position in circuit- around 35-45 cm from Y connector or ETT Continuous/ intermittent operation duration of nebulization

INHALATIONAL ANTIBIOTICS IN INHALATIONAL ANTIBIOTICS IN ICU ICU

SPECIFIC DOSING OF DRUGS:

Amikacin- 400 mg q8-12h Gentamycin- 80 mg q8h Tobramycin ( TOBI)- 300 mg q 12h colistin- 150 mg ( 2 mu) q 8-12h Vancomycin- 125 mg q8h
EACH DOSE SHOULD BE DILUTED TO A TOTAL VOLUME OF 4 ml

Aerosolized antibiotic therapy in ICU- guidelines prepared by Surgical Education, Orlando Regional Medical Centre. Approved 05-05-2009