inhalational therapy in icu

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INHALATIONAL ANTIBIOTICSIN ICU



WHY NEW ROUTE

COLONIZATIONOROPHARHYNGEAL

TRACHEOBRONCHEAL

Tracheobronchitis

Pneumonea

PROPHYLAXIS

TREATMENT

INHALATIONAL ANTIBIOTICS IN ICU



n Higher therapeutic dose– dose delivery to target organ

higher Vd in critically ill patient

n Higher dose delivery to distal airways and lung parenchyma- lower therapeuticdose

n Lower risk of systemic side effects

WHY NEW ROUTE

Inhaled therapy

Systemic Antibiotics


ADVERSEEFFECTS



Lung distribution and pharmacokinetics of Lung distribution and pharmacokinetics of nebulizednebulized tobramycintobramycin--Le Conte P, Am revLe Conte P, Am rev respresp dis1993, 147:1279dis1993, 147:1279--8282

IS IT EFFECTIVE

Concentration of Concentration of gentamycingentamycin in bronchial secretion after intramuscular andin bronchial secretion after intramuscular and endobronchialendobronchial

administrationadministration-- KlasterskyKlastersky J, JJ, J clinclin pharmacolpharmacol, 1975, 15, 518, 1975, 15, 518--2424

GentamycinGentamycin 2mg/kg: concentration achieved2mg/kg: concentration achieved-- endobronchialendobronchial secretion serumsecretion serum

I.M. routeI.M. route <2ug/ml >6ug/ml<2ug/ml >6ug/ml

EndobronchialEndobronchial routeroute >400ug/ml <1ug/ml>400ug/ml <1ug/mlTo prevent toxicity DESIRED TROUGH SERUM CONCTo prevent toxicity DESIRED TROUGH SERUM CONC-- < 1< 1--22 ugug /ml /ml

(( GoodmannGoodmann and Gilmanand Gilman’’s the pharmacological basis of therapeutics 11s the pharmacological basis of therapeutics 11thth ediedi--2006)2006)

Mean lung tissue conc. 5.5ug/ml after 4 hours ;Mean lung tissue conc. 5.5ug/ml after 4 hours ; 33--61ug/ml after 12 hours61ug/ml after 12 hours

InhaledInhaled amikacinamikacin achieves high epithelial lining fluid concentration in Gramachieves high epithelial lining fluid concentration in Gram negneg pneumoneapneumonea

inin intubatedintubated an mechanically ventilated patients.an mechanically ventilated patients.LuytLuyt CE, Jacob A, Am JCE, Jacob A, Am J RespirRespir CritCrit Care Med 2007; 175:A 328Care Med 2007; 175:A 328




IS IT EFFECTIVE

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

Aerosolized antibiotic in mechanically ventilated patients: deliAerosolized antibiotic in mechanically ventilated patients: delivery and response.very and response.

Lucy B. Palmer, Gerald C.Lucy B. Palmer, Gerald C. SmaldoneSmaldone,, critcrit care med; 1998; 26:1:31care med; 1998; 26:1:31--3939

AerosolizedAerosolized amikacinamikacin andand gentamycingentamycin for 14for 14--21 days in 9 cycles in mechanically21 days in 9 cycles in mechanically venilatedvenilated

stable patients colonized with Gstable patients colonized with G negneg organism producing purulentorganism producing purulent secrectionsecrection




PAST

n Documented efficacy in cystic fibrosis

n

Data are scarce in critically ill patients on mechanicalventilation

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)




Falagas ME, Siempos II, Bliziotis IA, Michalopoulos: Administration of

antibiotics via the respiratory tract for the prevention of ICU-acquired pneumonia:

a meta-analysis of comparative trials. Crit Care 2006; 10:R123.

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

PREVENTION OF COLONIZATION AND

NOSOCOMIAL PNEUMONEA




PREVENTION OF NOSOCOMIAL PNEUMONEA

Characteristics of comperative trial included in meta analysis

Polymyxin B 2.5 mg/kg bw/d in 6 divided doses1973 58Greenfield et al

Gentamycin 80 mg q8h1974 85Klatersky et al

Polymyxin B 2.5 mg/kg bw/d in 6 divided doses1975 692Klick et al

Gentamycin 40 mg q6h1981 40Vogel et al

Gentamycin 40 mg q6h1992 162Lode et al

Tobramycin 80 mg q6h1993 69Rathgerber et al

Colistin 0.2 mu q3h1994 598Rouby et al

Ceftazidime 250 mg q12h2002 40Wood et al

Study drug/ doseYear Pt. no.Reference





TREATMENT OF TRACHEOBRONCHITIS

Palmer LB, Smaldone GC, Chen JJ, et al.

Aerosolized antibiotics and ventilator-associated tracheobronchitis in the ICUCrit Care Med 2008; 36:2008–2013.

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.

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

No difference in WBC before or after therapy

No difference in mortality





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




Ioannidou E, Siempos II, Falagas ME. Administration of antibiotics via the

respiratory tract for the treatment of patients with nosocomial pneumonia: a

meta-analysis. J Antimicrob Chemother 2007; 60:1216–1226.


TREATMENT OF NOSOCOMIAL PNEUMONEA

No difference was demonstrated for mortality,

emergence of resistance, or adverse event.

META ANYLYSIS OF 5 TRIALSStatistically higher success rate for the

treatment of nosocomial pneumonia

if receiving inhaled or endotracheally instilled antibiotics

in the 176 patients.




Falgas ME, Agrafiotis M, Athanassa Z, et al

Administration of antibiotic through respiratory tract as monotherapy for pneumoneaExper Rev Antiinf Ther 2008;6:447-452


MONOTHERAPY OF NOSOCOMIAL PNEUMONEA

TREATING PATIENT WITH VAP WITH AEROSOLIZED ANTIBIOTIC ALONE IS

PREMATURE

This therapy might be considered when systemic access is not available,

refused by the patient or concern regarding bioavailability to lung or

systemic toxicity




Role of inhaled anibacterial in hospital aquired and ventilator associated

pneumonea .

Lesho E. Expert Rev Anti Infect Ther 2005;3(3):445-451


RECOMMENDATION FOR PREVENTION OF NOSOCOMIAL

PNEUMONEA

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

Despite optimized delivery systems…inhaled antibiotics can still not be recommended for

preventing VAP

Recent evidence base reviews have interpreted supporting data as week

Universally recommended against routinely using for VAP prophylaxix untill stronger data

are available




NO RECOMMENDATION

ABOUT ANTIBIOTIC

INDICATION ,SELECTION, DOSE,

FREQUENCY, DURATION

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 concernLegal concern--

airway as a route of airway as a route of AntiobioticAntiobiotic delivery not approveddelivery not approvedby USFDAby USFDA

(EVEN FOR TOBRAMYCIN FOR WHICH SPECIFIC PREPARATION(EVEN FOR TOBRAMYCIN FOR WHICH SPECIFIC PREPARATION

TOBITOBI IS AVAILABLE)IS AVAILABLE)




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 ICUINHALATIONAL ANTIBIOTICS IN ICU




PROBLEMS

BRONCHOSPSMPretreatment with albuterol 2.5 mg

SYSTEMIC TOXICITY AND INTRODUCTION OF NEW INFECTION

PATIENT RELATED DEVICE RELATED DRUG RELATED

DRUG DELIVERY

VENTILATOR RELATED CIRCUIT RELATED

EMERGENCE OF

RESISTANCE





PROBLEMS- DRUG DELIVERY

PATIENT RELATED:•Airway obstruction

•Dynamic hyperinflation

•PVA

VENTILATOR RELATED:•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

DEVICE RELATED:

• Type of nebulizer- Jet/ ultrasonic

• Flow – 6-8 lt

• Position in circuit- around 35-45 cm from

Y connector or ETT

• Continuous/ intermittent operation

• duration of nebulization

CIRCUIT RELATED:•ETT-

• Inhaled gas humidity• Inhaled gas density/ viscocity

• DRUG RELATED:• Dose

• Particle size- 1-5 micron

• Volume- 4-5 ml( neb charge)


Tubing acts asspacer deviceand increases

respirablefraction



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


inhalational therapy in icu

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