Inhalational therapies for the icu (2)

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.


WHY NEW ROUTE

COLONIZATION

PROPHYLAXIS

OROPHARHYNGEAL

TRACHEOBRONCHEAL

Tracheobronchitis
TREATMENT

Pneumonea


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


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 achieved-

endobronchial 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 Gilman’s 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


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


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)


PREVENTION OF COLONIZATION AND
NOSOCOMIAL PNEUMONEA
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 NOSOCOMIAL PNEUMONEA
Characteristics of comperative trial included in meta analysis
Reference

Year Pt. no.

Study drug/ dose

Wood et al

2002

40

Ceftazidime 250 mg q12h

Rouby et al

1994

598

Colistin 0.2 mu q3h

Rathgerber et al

1993

69

Tobramycin 80 mg q6h

Lode et al

1992

162

Gentamycin 40 mg q6h

Vogel et al

1981

40


Klick et al

1975

692

Polymyxin B 2.5 mg/kg bw/d in 6 divided doses

Klatersky et al

1974

85


Greenfield et al

1973

58

Polymyxin B 2.5 mg/kg bw/d in 6 divided doses


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.

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


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



TREATMENT OF NOSOCOMIAL PNEUMONEA
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.

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.



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



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 systems…inhaled 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


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)

NO RECOMMENDATION
ABOUT ANTIBIOTIC

Legal concern-

airway as a route of Antiobiotic delivery not approved
by USFDA

INDICATION ,SELECTION, DOSE,
FREQUENCY, DURATION

(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 )


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



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

DEVICE RELATED:

Tubing acts as
spacer device
and increases
respirable
fraction

• 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


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 therapies for the icu (2)

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