2Patient profileName 陳XX Admission date 2013/03/16Age 74 y/o Height/ Weight 160 cm/ 57kgGender Male Allergy history NKDABMI 22.3 Status Nursing home residentPast history• Rt medulla infarction with Lt hemiparesis, Lt limb and Rt facial paresthesia,dysphagia, and dysarthria• Subglottic stenosis, s/p T-tube implantation, currently on tracheostomy• Type 2 DM• HTN• HyperlipidemiaChief complaint• Left lower lung pneumonia patch noted at OPD• Dyspnea and symptoms aggravated despite oral FQ use3/13 OPDLevofloxacin 500mg QD AC
Outline Rationale for using the nebulized route Aerosolized antibiotics to treat HAP/ VAP Administration considerations Safety concerns SummaryHAP – hospital-acquired pneumoniaVAP – ventilator-associated pneumonia 6
Bad Bugs, No Drugs: No ESKAPE! Regulatory approvals for antibioticshave declined Clinically relevant resistance hasincreased7Enterococcus faeciumStaphylococcus aureusKlebsiella pneumoniaeAcinetobacter baumaniiPseudomonas aeruginosaEnterobacter species“ESCAPE” the effects ofantibacterial drugs
Potential Pathogen Recommended empiric antibiotic therapyNO RISK FOR MDR PATHOGENSStreptococcus pneumoniaeHaemophilus inﬂuenzaeMSSAAntibiotic-susceptible, enteric GNB:Escherichia coliKlebsiella pneumoniaeEnterobacter speciesProteus speciesSerratia marcescensMONOTHERAPYCeftriaxoneorLevofloxacin, moxifloxacin, ciprofloxacinorAmpicillin/sulbactamorErtapenemRISK FOR MDR PATHOGENPseudomonas aeruginosaKlebsiella pneumoniaeAcinetobacter speciesMRSACOMBINATION THERAPYCefepime, ceftazidimeImipenem, meropenemPiperacillin-tazobactamplusCiprofloxacin, levofloxacinAmikacin, gentamicin or tobramycinplus (if risk of MRSA)Linezolid or vancomycinAm J Respir Crit Care Med. 2005;. 171:388-416. 8Pathogens and antibiotic therapy for HAP/VAP/ HCAP
Many antibiotics used to treat HAP have poor penetration intothe epithelial lining ﬂuid (ELF) of the lungs ELF/plasma penetration ratio > 1Macrolides, Fluoroquinolones, Oxazolidinones ELF/plasma penetration ratio ≤ 1Beta-lactams, Aminoglycosides, Glycopeptidesa Clin Pharmacokinet. 2011 Oct;50(10):637-64.b Chest 2004;125:965-973.c Antimicrob Agents Chemother. 2008 Jan;52(1):24-36.CID 2010; 51(S1):S103–S1109Lung penetration of antibioticsDrug AUCelf/AUCsPIP/TAZ 0,568±0,336/ 0,913 ±0,277CeftazidimeCefepime0,206 ±0,0891.01ErtapenemMeropenem0.320.32-0.53GentamicinTobramycin0.74±0.180.64±0.37VancomycinTeicoplanin0.181.46Drug AUCelf/AUCsCiprofloxacinGatiﬂoxacinLevofloxacinMoxifloxacin0.82c1.77c2.08c5.18cClarithromycinAzithromycin1413.3bLinezolidTigecycline1.04±0.281.32cELF: suggested as the site (compartment) of antimicrobial activity against lunginfections caused by extracellular pathogens• A time lag between the serumconcentration curve and extravascularconcentration curve• Ratio of AUC is a better parameter torepresent tissue penetration of antibioticssingle dose oral cefdinir 300mgplasmablister ﬂuid(extravascularcompartment)Antimicrob Agents Chemother. 1995 May; 39(5): 1082–1086.CextravascularCplasma< 1CextravascularCplasma> 1
Optimize the delivery of currently available antibioticsTarget drug delivery directly to the site of action10Rationale for using the nebulized route• Achieve high local drug concentrationMaximize efficacy• Reduce systemic antimicrobial exposureMinimize systemic toxicitySerum vs Sputum Concentrations of TobramycinRoute Dosage Peak serum conc (µg/ml) Peak sputum conc (µg/g)IV 6–10.8 mg/kg/day 7.5 82Aerosol 300 mg bid 0.58 ± 0.380.74 ± 0.431.01 ± 0.576664801199.2Am Rev Respir Dis 1985;132:761–7.Chest 1997;111:955–62.Pediatr Pulmonol 1997(suppl 14):137–8.Curr Opin Biotechnol. 2008 Dec;19(6):637-43.
Therapeutic use AntibioticCystic fibrosisPrevent and treat infection due to P. aeruginosaTobramycinAztreonamColistinNon–cystic fibrosis bronchiectasissuppression therapyTobramycinGentamicinAmikacinColistinHospital-acquired pneumoniaTobramycinGentamicinAmikacinColistinCefotaximeCeftazidimeNontuberculosis mycobacterial infection AmikacinProphylaxis of invasive pulmonary aspergillosis Amphotericin BPrevention of PJP PentamidinePharmacotherapy. 2010;30(6):562-584. 11Antibiotics used for aerosolization in clinical studies*FDA-approved to be inhaled
“To achieve adequate therapy, it is necessary not only to use the correct antibiotic,but also the optimal dose and the correct route of administration (oral, intravenous,or aerosol) to ensure that the antibiotic penetrates to the site of infection, and touse combination therapy if necessary” “Local instillation or aerosolization is a way to enhance antibiotic penetration tothe lower respiratory tract … Aerosolized antibiotics may also be useful to treatmicroorganisms that, on the basis of high MIC values, are ‘resistant’ to systemictherapy”ATS/IDSA. Am J Respir Crit Care Med 2005;171:388–416. 132005 ATS/IDSA guidelines recognize apotential role for inhaled antibioticsRecommendations• Adjunctive therapy with an inhaled aminoglycoside or polymyxin forMDR gram-negative pneumonia should be considered, especially inpatients who are not improving with systemic therapy (Level III)
14Aerosolized AminoglycosideStudy (year) Study designPatient(%ventilated)Inhalation therapySystemictherapyDurationClinicalcure rateAdverseeventPines et al.(1970)Retrospective 12 (NR) GM 40mg qid Carbenicillin 7-10 67% NoneKlastersky et al.(1972)RCT 15 (NR) GM 40mg q3h None NR 100 vs 25 NRKlastersky et al.(1979)RCT 38 (45) Sisomicin 25mg q8hCarbenicillinSisomicin7 77 vs 45 NRMohr et al.(2007)Retrospective 22 (100)Tobramycin 300mg q12hor Amikacin 1000mg q12hVaried 7 59% NoneCzosnowski et al.(2009)Retrospective 62 (100)Tobramycin 300mg q12hor Amikacin 1000mg q8hor Colistin 150mg q12hVaried 10First episode:73%Subsequent episode:73%Failed IV monotherapy:85%MDR organisms:79%NoneBr Med J. 1970 Mar 14;1(5697):663-5.Chest. 1972 Feb;61(2):117-20.Chest. 1979 May;75(5):586-91.Surg Infect (Larchmt). 2007 Jun;8(3):349-57.Pharmacotherapy. 2009 Sep;29(9):1054-60.
Respir Med. 2008 Mar;102(3):407-12.J Microbiol Immunol Infect. 2010 Aug;43(4):323-31.16Aerosolized Colistin- recent studiesMichalopoulos et al. (2008) Lin et al. (2010)Study design Prospective observational Retrospective observationalCountry Greece TaiwanPatient• 60 VAP critically ill patients• APACHE II score: 16.7• 37 A. baumanii12 P. aeruginosa11 K. pneumonia50% susceptible only to colistin• 45 patients with VAP• APACHE II score: 18.9 ± 5.7• MDRABall susceptible only to colistinInhalationtherapyColistin 2.2 MU/ day(1.5-3 MU/ day)Mean duration 10.29 daysColistin 4.29 ± 0.82 MU/ day(2-6 MU/ day)Mean duration 10.29 daysSystemic therapy57 Colistin + other antibiotic3 Meropenem6 Colistinother mainly carbapenemOutcome• Clinical cure: 83%• All cause mortality: 25%VAP related mortality: 16.7%• Clinical cure: 57.8%• All cause mortality: 42.2%VAP related mortality not reportedComment No adverse effects related to inhaled colistin were recorded
Clin Infect Dis. 2010 Dec 1;51(11):1238-44.17ObjectiveCompare the efﬁcacy and safety of AS (aerosolized) plus IV colistin vs. IVcolistin alone for patients with MDR VAP due to gram-negative bacteriaStudy designRetrospective matched case-control studyFrom Jan. 2005 through Dec. 2008Patient• Culture-documented monomicrobial VAP due toA. baumanii, P. aeruginosa, or K. pneumoniaethat was susceptible only to colistin• 86 patients with VAP (43 AS-IV colistin vs 43 IV colistin alone)• Matching criteria: age (± 5 yr) and APACHE II score (± 4 points)Treatmentregimen• Aerosolized: Colistin 1MU q12h• IV: Colistin 3MU q8hClin Infect Dis. 2010 Dec 1;51(11):1238-44.
Clin Infect Dis. 2010 Dec 1;51(11):1238-44.18Result
Clin Infect Dis. 2010 Dec 1;51(11):1238-44. 19OutcomeNo signiﬁcant differences between the 2 groupsNo adverse events were associated with aerosolized colistin therapy
Clin Infect Dis. 2010 Dec 1;51(11):1238-44. 20OutcomeVAP-related mortalityAll-cause mortalityP= .888 P= .268ConclusionsAddition of AS colistin to IV colistin did not provide additional therapeuticbeneﬁt to patients with MDR VAP due to gram-negative bacteria.
Palmer et al. (2008)Study design RCT performed from 2003 through 2004Patient • 43 critically ill intubated patients with VATDosing regimen• Randomized to receive aerosolized antibiotic (n=19) or saline (n= 24)• Antibiotic chosen by gram-stainGentamicin 80 mg q8h for gram-negativeVancomycin 120mg q8h for gram-positive• Aerosolized by aerotech II nebulizer• Duration: 14 days or until extubation• Both placebo and active treatment group received similar amounts ofappropriate systemic antibiotics at randomizationFollowed • 28 daysOutcomePrimary• Reduced VAP (73.6% to 35.7%) vs. Placebo (75% to 78.6%)• Reduced clinical pulmonary infection scoreSecondary• Reduced bacterial resistance• Reduced use of systemic antibiotics• Lower WBC at day 14• Facilitated weaningComment • No patients were withdrawn from the study for adverse events.VAT – ventilator-associated tracheobronchitis Crit Care Med 2008; 36:2008–2013.21Aerosolized vancomycin in gram-positive bacteriaall p < .05
This investigation also provided the ﬁrst promising data for thetreatment of MRSA via aerosolized vancomycin in ventilatedpatientsCrit Care Med 2008; 36:2008–2013.Curr Opin Crit Care. 2009 Oct;15(5):413-8. 22Aerosolized vancomycin in MRSA- Palmer et al. (2008)Aerosolized antibiotics PlaceboMRSA isolated atrandomization3 3• 2 patients without VAP at randomizationand remained free of VAP at the end oftreatment• 1 patient who had MRSA and had VAP hadclinical resolution at end of aerosolizedvancomycin treatment as well aseradication of the MRSA3 patients who had VAT secondary toMRSA as well as VAP at the time ofrandomization had no improvementduring the study despite being onsystemic antibiotics
How much drug actually reaches the site of infection? Dosage, drug delivery, pulmonary deposition Highly variable with over a tenfold difference in deliverydepending on the administration techniques use How long does the antibiotic stay in the lung? Clearance from the lung Systemic exposure Active in infected lung tissue? Stability and activity in pulmonary secretions and specialenvironments in the lungExpert Rev Anti Infect Ther. 2011 Nov;9(11):993-1000.Am J Respir Crit Care Med. 2003 Nov 15;168(10):1205-9.Curr Opin Biotechnol. 2008 Dec;19(6):637-43. 24Aerosolized delivery of antibiotics
Method of aerosol delivery Humidifying leads to aerosol losses and decrease drug delivery by up to 40% Breath-actuated nebulization administer a higher dose than continuousnebulization Type of nebulizer Characteristic of aerosolized particles Mean mass aerodynamic diameter(MMAD) Determine regional deposition within the lung Average size of particles generated by a drug-nebulizer combination Patient-specific factors Degree of airway obstruction Breathing pattern Lung transplant recipientsPharmacotherapy. 2010;30(6):562-584.Transplantation 2003;75: 1571–4.Am J Transplant 2006;6:2765–73.25Factors Related to Aerosolized Delivery
Le Brun PP et al. Pharm World Sci 2000;22:7–81Dhand R. J Aerosol Med 2008;21:1–16Pharmacotherapy. 2010;30(6):562-584.26Type of nebulizer• Aerosol generated by compressed air forced through asmall hole to a liquid drug reservoir• Delivery efficiency dependent on pressure of the drivinggas and the fill volume• Dead volume: 1-3 mlJet nebulizer• Piezoelectric crystal vibrate at high frequency to produceaerosol from liquid drug• Variable delivery efficiency• Generate heat and possible of denaturation ordegradation of proteins and peptidesUltrasonic nebulizer• Aerosol generated by flow of liquid drug through avibrating mesh (micropump) aperture• Better delivery efficiency than jet and ultrasonicnebulizersVibrating mesh nebulizer
Method of aerosol delivery Humidifying leads to aerosol losses and decrease drug delivery by up to 40% Breath-actuated nebulization administer a higher dose than continuousnebulization Type of nebulizer Characteristic of aerosolized particles Mean mass aerodynamic diameter(MMAD) Determine regional deposition within the lung Differ for each drug-nebulizer combination Patient-specific factors Degree of airway obstruction Breathing pattern Lung transplant recipientsPharmacotherapy. 2010;30(6):562-584.Transplantation 2003;75: 1571–4.Am J Transplant 2006;6:2765–73.27Factors Related to Aerosolized Delivery
Pharmacotherapy. 2010;30(6):562-584.28Aerosol particle size determine lung deposition> 5 µm impactiondeposited intooropharynx andswallowed1-5 µm sedimentationOptimal for delivery tothe lower airways andparenchyma< 0.8 µmlikely to be exhaled bytidal breathing
Method of aerosol delivery Humidifying leads to aerosol losses and decrease drug delivery by up to 40% Breath-actuated nebulization administer a higher dose than continuousnebulization Type of nebulizer Characteristic of aerosolized particles Mean mass aerodynamic diameter(MMAD) Determine regional deposition within the lung Average size of particles generated by a drug-nebulizer combination Patient-specific factors Presence of airway obstruction Breathing pattern Lung transplant recipientsPharmacotherapy. 2010;30(6):562-584.Transplantation 2003;75: 1571–4.Am J Transplant 2006;6:2765–73.29Factors Related to Aerosolized Delivery
The aminoglycosides MIC increased to 10–25-fold higher than thoseobserved in vitro Binding of cationic moieties on the aminoglycosides to anionic substances(e.g. Nucleic acids) present in high concentrations in the sputum of CFAm Rev Respir Dis 1985;132(4):761–765.J Infect Dis 1983;148(6):1069–1076.Respir Care 2007; 52:866–884.Current Opinion in Biotechnology 2008, 19:637–64330Reduced activity of aminoglycoside in sputumC ≥ 25 x MIC were required toproduce a reliable bactericidaleffect in the presence ofsputumInhibition of tobramycin activity by sputumfrom cystic fibrosis patients
AUC, Cmax → Drug exposure MIC → Antimicrobial potency against key pathogens Higher concentrations achievable by the aerosol route Current ‘breakpoint’ definition do not apply for aerosol administrationCurrent Opinion in Biotechnology 2008, 19:637–643. 31Pharmacokinetic/ Pharmacodynamic ParametersDrug class Bacterial killing abilitySuppress selection ofresistant strainsConcentration-dependentAminoglycosideFluoroquinoloneAUC:MIC, Cmax:MIC Cmax: MICTime-dependentBeta-lactamMonobactam% T> MICNot rigorously studied, buthigher AUC:MIC orCmin:MIC may be useful
FDA ALERT 2007/06/28Potential connection between the use of aerosolizedcolistimethate and the death of a patient with cystic fibrosisU.S. Food and Drug Administration. Information for healthcare professionals on colistimethate 33 In April 2007, a patient with CF had a home nebulizer treatmentwith a premixed liquid form of ready-to-use colistimethate suppliedby a pharmacy. Within hours, the patient developed respiratory distress thatprogressed over several days to acute respiratory failure. The patient had copious amounts of thin pink pulmonary secretionsand was admitted to intensive care. Bronchoscopy revealed clearcentral airways and no unusual pathogens. Pulmonarycomputerized tomography scan findings showed ground glassinfiltrates, consistent with acute respiratory distress syndrome. The patient expired of multi-organ system failure about 19 days later.
Polymyxin E1 cause localized inflammation of the airway epithelia andeosinophilic infiltration Storing colistimethate aqueous solution for longer than 24 hours→ Increased concentrations of colistin A in solution→ Potentially serious and life-threatening side effectsPrevention Colistin should be administered promptly after it is reconstituted34Lung toxicity of colistinColistinmethanesulfonate(CMS)ColistinInactive pro-drugSpontaneous hydrolysisin aqueous solution ActiveColistin A (Polymyxin E1)Colistin B (Polymyxin E2)Lung Toxicity!!
35Plausible Mechanisms of Adverse Effects• Direct exposure to the drug or excipientLocal respiratory effect• Systemic absorption from lungSystemic effect
Airway irritation Cough, bad taste, wheezing, shortness of breath Bronchospasm Due to preservatives contained in IV formulation EDTA, benzalkonium chloride, phenol, sulfite Possible life-threatening Higher risk population: smokers, asthma, COPDPrevention Pretreated with bronchodilator, such as albuterol Specialized formulation Adjusted Osm, content of chloride ions, pH, preservative-freeClin Med Res 2006; 4:138–146.Curr Op Infect Di 2009; 22:154–158. 36Local respiratory effect
Very few antibiotics have formulations developedspecifically for administration aerosol Particle size, viscosity, surface tension, osmolality, tonicity,and pH… IV formulations are not optimized for aerosolized Impede drug delivery Contain preservative Cause adverse effectPharmacotherapy. 2010;30(6):562-584. 37Off label use IV preparation as an aerosol
Drug IndicationDosefrequencyPhaseTobramycin nebulizer solution(TOBI®)Cystic fibrosisBIDApprovedTobramycin inhalation powder(TOBI® Podhaler™ )Cystic fibrosis BID ApprovedAmikacin inhalation solution(NKTR-061, BAY41-6551)Hospital-acquired pneumonia Q12H Phase 3Liposomal Amikacin for inhalation(Arikace)Cystic fibrosis and NTMQDApprovedCiprofloxacin DPI(BAY Q3939)Cystic fibrosisBIDApprovedLiposomal ciprofloxacin for inhalationCystic fibrosisnon-CF bronchiectasisQD ApprovedLevofloxacin inhalation solution(MP-376, Aeroquin)Cystic fibrosis BID Phase 3Aztreonam lysine(Cayston)Cystic fibrosis BID Approved38Formulations for inhalation
Pharmacotherapy. 2010;30(6):562-584. 39Adverse effects have been reportedAminoglycoside Colistin• Nephrotoxicity and Ototoxicityin case reportsHigher rate of adverse events reported thanaminoglycoside• Bronchospasm• Chest tightness• Nephrotoxicity• Apnea due to neuromuscular blockadePrevention• Monitor BUN and Scr in long-term therapy• Avoid hypokalemia, hypomagnesimia• Baseline and periodic audiometric evaluations• Monitor serum level if drug accumulation is suspected, particularly in renaldysfunction• Avoid concomitant drugs with nephrotoxicity or ototoxicity
Contamination of the delivery device Reusing disposable devices, inadequate cleaning, and withimproper administration Risk of subsequent infection or reinfection Environmental problem Secondary exposure other than patients (health careworkers, pregnant woman) Potential to change the microbial flora with selection ofresistant pathogensPharmacotherapy. 2010;30(6):562-584. 40General Safety Concerns
Prolonged use of broad-spectrum antibiotics is know to leadto emergence of multiresistant strains, and nebulization is notan exception Gentamicin in prevention of HAP/VAP 1,2,3 Long term tobramycin in CF patients 4 Mucus plugging and/or atelectasis will hinder deposition This may lead to lower concentrations, allowing selection of resistantclones Environmental exposure must also be minimized1. Chest 1974; 65: 650–42. Chest 1975; 68:302–63. J Trauma 1978; 18:188–934. JID 1999; 179: 1190-11965. Dr Justin JD Daniels. The Potential Of Inhaled Antimicrobial In A Age Of Multi-drug Resistant Bacteria 41Emergence of resistant strains
42Common dosage of aerosolized antibioticsOur patient:Colistin 2mu q12h inhlAntibiotic Common nebulized dosageTobramycin80mg/2mL/vial300mg q12hGentamicin80mg/2mL/amp80mg q12hAmikacin500mg/2ml/vial500mg-1000mg q12hColistin2MU(66.8mg)/vial1-2 MU 2-3 times daily, Max: 6 MU / dayColimycin 1 vial= Colistimethate sodium 160 mg (2 MU)= Colistin base 66.8 mgOur patient:Colistin 2MU q12h inhl
Improving delivery Use a ﬂow rate greater than 6 l/min and nebulize only duringinspiration Use a jet nebulizer with a MMAD 1–5 µm Compound to the maximum fill volume for the nebulizer Discontinue humidiﬁcation during drug administrationImproving tolerance Pretreatment with albuterol for patient with previous adversereaction or chronic lung disease pH of drug: 4.0–8.0, Na: 77-154 mEq/l, Osm: 150–1200 mOsm/l Use normal saline for drug dilution Use colistin immediately after preparation Monitor patient for adverse responseExpert Rev Anti Infect Ther. 2011 Nov;9(11):993-1000. 43Recommendations for administration
Aerosolized antibiotic may be considered As adjunctive therapy in combination with systemicantimicrobial to treat HAP/ VAP In patients with MDR gram-negatives who are notresponding to systemic therapy Colistin and aminoglycosides are the drug of choice Adverse events can occur, especially with colistin Care should be taken to properly compound and administeraerosolized antibiotics to ensure tolerability and good drugdeliveryATS/IDSA. Am J Respir Crit Care Med 2005;171:388–416.Can J Infect Dis Med Microbiol. 2008 Jan;19(1):19-53. 44Summary