inhalational therapies for the icu (2)

INHALATIONAL ANTIBIOTICS IN ICU

Ubaidur RahamanSenior Resident Dept of CCM, SGPGIMS, Lucknow,India

Respiratory tract as a conduit for therapeutic drug delivery

not a new concept

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


WHY NEW ROUTE

COLONIZATION OROPHARHYNGEAL

TRACHEOBRONCHEAL

Tracheobronchitis

Pneumonea

PROPHYLAXIS

TREATMENT


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 therapeutic dose

n Lower risk of systemic side effects

WHY NEW ROUTE

Inhaled therapy

Systemic Antibiotics


ADVERSE EFFECTS

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

IS IT EFFECTIVE

Concentration of Concentration of gentamycingentamycin in bronchial secretion after intramuscular and in bronchial secretion after intramuscular and endobronchialendobronchialadministrationadministration-- KlasterskyKlastersky J, J J, J clinclin pharmacolpharmacol, 1975, 15, 518, 1975, 15, 518--2424

GentamycinGentamycin 2mg/kg: concentration achieved2mg/kg: concentration achieved-- endobronchialendobronchial secretion serum secretion serum I.M. route I.M. route <2ug/ml >6ug/ml<2ug/ml >6ug/mlEndobronchialEndobronchial route route >400ug/ml <1ug/ml >400ug/ml <1ug/ml To prevent toxicity DESIRED TROUGH SERUM CONCTo prevent toxicity DESIRED TROUGH SERUM CONC-- < 1< 1--2 2 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

Inhaled Inhaled amikacinamikacin achieves high epithelial lining fluid concentration in Gram achieves high epithelial lining fluid concentration in Gram negneg pneumoneapneumoneain in intubatedintubated an mechanically ventilated patients.an mechanically ventilated patients.

LuytLuyt CE, Jacob A, Am J CE, Jacob A, Am J RespirRespir CritCrit Care Med 2007; 175:A 328 Care 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, enterobactoraerogenes

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

Aerosolized Aerosolized amikacinamikacin and and gentamycingentamycin for 14for 14--21 days in 9 cycles in mechanically 21 days in 9 cycles in mechanically venilatedvenilated

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


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)


Falagas ME, Siempos II, Bliziotis IA, Michalopoulos: Administration ofantibiotics 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 598 Rouby 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 ICU Crit 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 aerosolizedvancomycin or gentamycinfor 14 days versus placebo.Iv antibiotics prescribed on physician discretion

No difference in WBC before or after therapyNo difference in mortality



TREATMENT OF TRACHEOBRONCHITIS

Nseir S, Favory R, et. Antimicrobial treatment for ventilator associated tracheobronchitisA randomised controll multicentre study. Crit Care 2008;12:R62

Significant decrease in progression to VAPEarlier discontinuation of mechanical ventilation

Reduced mortality

Serial ETA monitoring to diagnose VAPRandomised to receive aerosolized therapy vs no therapy


Ioannidou E, Siempos II, Falagas ME. Administration of antibiotics via therespiratory 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 antibioticsin 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 weekUniversally 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 approved

by USFDAby USFDA

(EVEN FOR TOBRAMYCIN FOR WHICH SPECIFIC PREPARATION(EVEN FOR TOBRAMYCIN FOR WHICH SPECIFIC PREPARATIONTOBITOBI 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 treatVAP 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 as spacer device and 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
