Clinical experimentation with aerosol antibiotics: current and future methods of administration

Figures & data

Table 1 Aerosol studies with tobramycin, amikacin, and gentamicin

Reference	Drug	Subjects	Production system	Result	Dosage	LFTs	Major adverse effects
Ramsey et al^Citation27	Tobramycin	663 patients Mean age 21 years	PARI LC Plus and Pulmo-Aide	↑FEV1, decreased sputum PA density, fewer hospitalizations	300 mg inhaled tobramycin or placebo, 24 weeks	FEV1	Tinnitus, voice alteration and pneumothorax
Stelmach et al^Citation73	Tobramycin	6–18 years	–	Improved body mass index, reduced FEV1 decline over 2 years, delayed X-ray disease progression	300 mg inhaled tobramycin 28 days on and 28 days off drug, 2 years	FEV1	No major adverse effects reported
Murphy et al^Citation30	Tobramycin	184 patients recruited and 63 completed the 56-week evaluation	PARI LC Plus and Pulmo-Aide DeVilbiss	Increased FEF25–75 by8%, weight increase in both groups, fewer adverse events on aerosol tobramycin, fewer concomitant antibiotics	300 mg inhaled tobramycin<br/>28 days on and 28 days off drug, 56 weeks	FEV1, FVC, FEF25–75 SaO2	Cough, sore throat, sneeze, dizziness, pharyngitis, tinnitus, conjunctival hyperemia
McCoy et al^Citation37	Tobramycin Aztreonam lysinate	≥6 years First step, 246 enrolled Second step, 21 1 enrolled Mean age 26.2 years	PARI LC Plus and eFlow nebulizer system	CFQ-R and FEV1 increase after AZLI and delayed time to inhaled or intravenous antibiotic administration after AZLI	300 mg twice daily, 28 days<br/>75 mg twice or three times daily, 28 days	FEV,	6 patients, > 15% FEV1 reduction
Hodson et al^Citation43	Tobramycin Colistin	≥6 years, 115 patients	PARI LC Plus and Ventstream	FEV1 increase in the TOBI Group, and GRCQ improvement in TOBI group	TOBI 300 mg twice daily<br/>Colistin 80 mg twice daily 1 month plus an additional 4 weeks of follow-up	FEV1	Pharyngitis, 17 patients, ≥ 10% decrease after aerosol administration
Geller et al^Citation26	Tobramycin	523 patients, >6 years, Mean age 21 years	PARI LC Plus and Pulmo-Aide DeVilbiss	Efficient deposition, low plasma concentration, increased sputum MIC	300 mg twice daily<br/>28 days, 24 weeks	FEV1, FVC, FEV1/FVC ratio	–
Moss et al^Citation28,Citation25	Tobramycin	128 patients	PARI LC Plus and Pulmo-Ade DeVilbiss	Increase in FEV1 correlated with reduction in sputum PA density	300 mg, 96 weeks	FEV1	–
Briesacher et al^Citation74	Tobramycin	804 patients	–	Decreased days of hospitalization with more than four cycles of administration	2001–2006 data	–	–
Geller et al^Citation49	Tobramycin, both aerosol and dry powder	90 randomized	PARI LC PLUS and Pulmo-Aide DeVilbiss and T-326 DPI	Efficient pharmacokinetic evaluation of dry powder	300 mg aerosol and four capsules =112 mg equivalent to 300 mg of aerosol tobramycin	FEV1	Cough, dysgeusia, decline of FEV, after both aerosol and dry powder administration
Konstan et al; EVOLVE trial^Citation75	Tobramycin dry powder	102 patients	T-326 DPI	Increase in FEV1 reduction in sputum PA density	Four capsules = 112 mg	FEV1	Cough, sore throat, pyrexia
Konstan et al; EAGER Trial^Citation50	Aerosol tobramycin versus light-porous particle, dry powder	≥6 years, 553 randomized	PARI LC Plus and Pulmo-Aide DeVilbiss and T-326 DPI	Equal increase in FEV1, higher reduction in sputum PA density in TIP, higher treatment satisfaction in TIP group, TSQM	300 mg aerosol and four capsules =112 mg × 2 equivalent to 300 mg aerosol tobramycin 3 × 28 days	FEV1	Cough, dysphonia, dysgeusia, bronchospasm, equal in both groups, 5.2% TIP and 5.3% TIS
Bhavsar et al^Citation76	Human lysozyme, tobramycin	PA	Misty-Ox Nebulizer	Three groups: 60 mg rhLZ, 5 μg ΤBΜΝ, 60 mg rhLZ	Reduced PA density and inflammatory index	–	–
Parkins et al^Citation62	TOBI dry powder	Review	Review	Review	Review	Review	Review
Geller et al^Citation26	TOBI dry powder	Review	Review	Review	Review	Review	Review
Trapnell et al^Citation56	Fosfomycin/tobramycin	162 CF patients screened 121 completed ≥ 18 years, mean 32 years	eFlow nebulizer system (PARI)	↑FEV1, ↑CFQ-R, fewer symptoms with 80/20 mg	160/40 mg or 80/20 mg placebo, 28 days, twice daily	FEV1	Cough, dyspnea, wheezing less common with 80/20 mg
Newman et al^Citation116	Gentamicin	Eight nebulizers from each brand	Bird Micronebuliser DeVilbiss 646 Bard Inspiron Mini-Neb, Medic-Aid Upmist	The higher the flow rate the smaller the MMAD and shorter the nebulization time	–	–	–
Safdar et al^Citation82	Amikacin	9 patients Case series	Jet nebulizer	8 of 9 patients were efficiently treated	Amikacin 100 mg per 3 mL (intravenously) twice daily	–	Throat irritation, bitter taste, hoarseness of voice
Aquino et al^Citation78	Gentamicin dry powder	CuFi-1	Single-stage glass impinge and Turbospin®	Efficient manufacturing of gentamicin capsules	Storage stability	–	–
Ghannam et al^Citation77	Gentamicin, amikacin, Colistin, tobramycin	VAP pneumonia	Jet nebulizer	Efficient VAP pneumonia resolution in 81% aerosol versus 31%	Amikacin (100 mg/3 mL) Colistin (75 mg/4 mL) Gentamicin (40 mg/mL) Tobramycin (30 mg/5 mL)	–	–
Alhanout et al^Citation108	ASD and tobramycin	PA and SA	PARI LC Plus eFlow	For ASD, MIC remained the same after mucin addition MMAD <5 μm	ASD 2–10 mg/mL	–	–
Meers et al^Citation53	Liposomal amikacin	Animal	12-port nose-only inhalation chamber, PAI LC Star	Sustained release of liposomal amikacin based on supernatants	20 mg/mL	–	–

Abbreviations: FEV₁, forced expiratory volume in one second; FVC, forced vital capacity; FEF_25–75, forced expiratory flow during middle half of forced vital capacity; SaO₂, oxygen saturation; CFQ-R, Cystic Fibrosis Questionnaire-Revised; TOBI, inhaled tobramycin solution; AZLI, aztreonam lysinate; PA, Pseudomonas aeruginosa; TIP, inhaled tobramycin powder; TIS, inhaled tobramycin solution; TSQM, Treatment Satisfaction Questionnaire for Medication; DPI, dry powder; MMAD, mass median aerodynamic diameter; CuFi-1, human airway epithelial (HAE) cell line; SA, Staphylococcus aureus; VAP, ventilation-associated pneumonia; ASD, aminosterol derivative; MIC, minimum inhibitory concentration; LFTs, lung function tests.

Table 2 Aerosol studies with aztreonam lysinate

Reference	Drug	Subjects	Production system	Result	Dosage	LFTs	Major adverse effects
Gibson et al^Citation34	Aztreonam lysinate	21 adults and 19 adolescents	eFLOW nebulizer system (PARI)	Efficient drug evaluation, increased sputum and plasma drug levels after inhalation	75 mg/150 mg 225 mg	FEV1, FVC, FEF25–75 SaO2	Chest tightness, increased sputum, nasal congestion, aggravated cough, 1 patient >20% FEV1 reduction
Retsch-Bogart et al^Citation35	Aztreonam lysinate	105 randomized 14 days	eFLOW nebulizer system (PARI)	Decrease in sputum PA density, increase in FEV1 for AZLI patients in 7 days	75 mg/225 mg/twice daily placebo	FEV1, FVC, FEF25–75<br/>SaO2	Cough, transient decrease in FEV1
Retsch-Bogart et al^Citation36	Aztreonam lysinate	≥6 years 124 completed	eFLOW nebulizer system (PARI)	CFQ-R-respiratory scores improved and FEV1 improved, weight gain	75 mg/28 days	FEV1	Pulmonary exacerbation
Oermann et al^Citation38	Aztreonam lysinate	≥6 years, 195 completed Mean age 28.5 years	eFLOW nebulizer system	CFQ-R and FEV1 increase, reduction of sputum PA density	75 mg twice or three times daily, 18 months	FEV1, FVC, FEF25–75	Pyrexia, fatigue, headache, cough, decreased appetite
Oermann et al^Citation39	Aztreonam lysinate	≥6 years, 195 completed Mean age 28.5 years	eFLOW nebulizer system	30% increase in MIC, increase in tobramycin susceptibility	75 mg twice or three times daily, 18 months	–	–
Wainwright et al^Citation40	Aztreonam lysinate	≥6 years 157 patients	eFLOW nebulizer system	CFQ-R and FEV, increase, reduction of sputum PA density	75 mg three times daily, 28 days	FEV1	3 patients discontinued due to pulmonary exacerbation, one patient >20% FEV1 reduction
Parkins et al^Citation68	AZLI	Review	Review	Review	Review	Review	Review

Abbreviations: FEV₁, forced expiratory volume in one second; FVC, forced vital capacity; FEF_25–75, forced expiratory flow during middle half of forced vital capacity; SaO₂, oxygen saturation; CFQ-R, Cystic Fibrosis Questionnaire-Revised; TOBI, inhaled tobramycin solution; AZLI, aztreonam lysinate; PA, Pseudomonas aeruginosa; MIC, minimum inhibitory concentration; LFTs, lung function tests.

Table 3 Aerosol antibiotic studies with Colistin, amphotericin B, and antituberculosis drugs

Reference	Drug	Subject	Production system	Result	Dosage	LFTs	Major adverse effects
Jensen et al^Citation42	Colistin	14.2 mean years	Raindrop	Less decrease in FEV1, FVC with Colistin	One million units twice daily, 3 months/placebo	FEV1, FVC	Coughing, expectoration, rhonchi
Alexander et al^Citation72	Liposomal amphotericin B	–	Hudson Updraft, LC Star, Aeroeclipse II, Small Volume nebulizer	PARI LC and Aeroeclipse II	50 mg vials diluted in 12 mL	–	–
Gilani et al^Citation69	DC-SA nanomicelles + amphotericin B	Candida albicans, Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus Cryptococcus neoformans	Hudson London, UK	DC-SA more effective against Cryptococcus neoformans	Amphotericin B alone in water, Fungizone, DC-SA amphotericin B	–	–
Nasr et al^Citation66	Amphotericin B Nanoemulsions Intralipid® or Clinoleic®	In vitro evaluation Using a twin impinger	PARI LC Sprint and PARI Turbo Boy S compressor	Efficient drug loading and the Clinoleic displayed higher deposition of Amphotericin B in the lower impinge stage	Amphotericin B 25 mg added in 10 mL of Intralipid or Clinoleic nanoemulsions	–	–
Lu et al^Citation81	Colistin	165 enrolled with VAP PA and AB	Aeroneb Pro	Clinical cure rate 66% in sensitive strain and 67% in multidrug-resistant strain	400 mg every 8 hours 7–19 days	–	–
Wood et al^Citation80	VAP Aminoglycosides Colistin	Review	Review	Review	Review	Review	Review
Abdulla et al^Citation71	Rifampicin nanoparticles	Formulation evaluation	PARI LC Plus	MMAD <5 μm in any polymer weight ratio, sustained drug release	mPEG2000-DSPE and mPEG5000-DSPE	–	–
Pourshahab et al^Citation63	Isoniazid nanoparticles	PA, SA, and MI	DPI inhalation device Cyclohaler	MMAD 10 μm, Sustained drug release	Isoniazid-loaded chitosan/tripolyphosphate	–	–
Son et al^Citation57	Rifampicin microparticles	Membrane holder method	DPI inhalation device, Aerolizer	MMAD 3.5–4.5 μm	RFDH microcrystals coated PLGA or PLA	–	–
Son et al^Citation70	Rifampicin microparticles	Membrane holder method	DPI inhalation device, Aerolizer Handihaler	RFDH MMAD 2.2 μm	RFDH RFAM	–	–
Gonzalez-Juarrero et al^Citation101	Isoniazid, capreomycin, and amikacin	Mycobacterium tuberculosis	Intrapulmonary Microsprayer	Efficient for INH in both groups, additionally in spleen for aerosol	Isoniazid, capreomycin and amikacin 500 μg/dose 3 times weekly	–	–
Chan et al^Citation64	Isoniazid, rifampicin, pyrazinamide	Microparticle dissolution profile	Aerolizer	Efficient, excipient-free triple antibiotic DPI powder	Isoniazid 1.5 mg/mL, rifampicin 3 mg/mL, pyrazinamide 8 mg/mL	–	–
Hraiech et al^Citation107	Squalamine, Colistin	PA, rats	Nose-only jet nebulizer (cage)	3 μm MMAD Squalamine and 2.8 μm Colistin	160 mg Colistin and 3 mg squalamine 6 days	–	–

Note: Chitosan-stearic acid conjugate.

Abbreviations: FEV₁, forced expiratory volume in one second; FVC, forced vital capacity; AB, Acinetobacter baumannii; VAP, ventilation-associated pneumonia; MMAD, mass median aerodynamic diameter; PA, Pseudomonas aeruginosa; DPI, dry powder inhaler; RFDH, rifampicin dehydrate; PLGA, poly (_DL-lactide-co-glycolide); PLA, poly (_DL-lactide); RFAM, amorphous rifampicin; MI, Mycobacterium intraceiiuiare; LFTs, lung function tests.

Table 4 Aerosol studies with macrolides, quinolones, and tetracyclines

Reference	Drug	Subject	Production system	Result	Dosage	LFTs	Major adverse effects
Tsivkovskii et al^Citation83	Aerosol levofloxacin MP-376	HBE135 cells	Under clinical evaluation	Reduction in IL-6 and IL-8	–	–	–
King et al^Citation54	Levofloxacin, ciprofloxacin, amikacin, tobramycin, aztreonam	PA, BC, SM, AX, SA	–	Levofloxacin most potent MIC50 range from 8–32 μg/mL	Dosage as instructed in package	–	–
Peterson et al^Citation85	Levofloxacin, ciprofloxacin	BA, YP, FT	–	Effective dosage 90–120 mg/kg/day for both quinolones	5% levofloxacin 2% ciprofloxacin in 5% dextrose	–	–
Ong et al^Citation58	Liposomal ciprofloxacin	Calu-3	PARI LC Sprint and PARI Turbo Boy S compressor	Slower drug release from liposomes due to absence of in vivo trigger mechanisms	Ciprofloxacin 50 mg/mL, pH 6.0, HSPC 70.6 mg/mL, cholesterol 29.4 mg/mL	–	–
Togami et al^Citation21	Clarithromycin	Rat model	Liquid microsprayer	Aerosol more efficient delivery to ELF and AMs	Aerosol 0.2 mg/kg, Oral 50 mg/kg	–	–
Ren et al^Citation102	Doxycycline	Rats	Electric nebulizer	Prophylactic effect against treatment of smoking-induced mucus hypersecretion	Aerosol doxycycline 20 mg/kg	–	–
Zhang et al^Citation67	Azithromycin dry powder	In vitro In vivo	Microsprayer	High encapsulation 59.2% 3.82 μm	AZI, raw material purity 95.5%	–	–
Nemec et al^Citation106	Clindamycin	Mice, TNF-α, sTNFRI-sTNFR2, IL-Iβ, IL-6, PG	Microsprayer	Clindamycin alone better than clindamycin plus dexamethasone Normalized TNF-α, sTNFRs	Clindamycin 40 mg/kg	–	–
Togami et al^Citation91	Telithromycin	Rats, Hemophilus influenzae, Streptococcus pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, and Mycobacterium avium S. pneumoniae resistant to Penicillin G, erythromycin A and levofloxacin	Microsprayer	Aerosol distribution more efficient in AMs and ELF	Aerosol 0.2 mg/kg, Oral 50 mg/kg	–	–

Abbreviations: AMs, alveolar macrophages; ELF, epithelial lung fluid; TNF-α, tumor necrosis factor-α; MIC, minimum inhibitory concentration; SA, Staphylococcus aureus; PA, Pseudomona aeruginosa; BC, Burkholderia cepacia complex; SM, Stenotrophomonas maltophila; AX, Alcaligenes xylosoxidans; 1L-1β, interleukin 1β; 1L-6, interleukin 6; BA, Bacillus anthracis; YP, Yersinia pestis; FT, Francisella tularensis; Calu-3, sub-bronchial epithelial cell line; HBE135 cells, human bronchial epithelial cells; LFTs, lung function tests.

Table 5 Methods and models of aerosol deposition evaluation

Durand M, Pourchez J, Aubert G, Le Guellec S, Navarro L, Forest v, Rusch P, Cottier M. Deposition evaluation model with classic nebulizer or 100 Hz acoustic airflow.^Citation59

McCormack P, McNamara PS, Southern KW. Two different breathing modes were evaluated.^Citation61

Willis LD, Berlinski A. Survey on aerosol administration in tracheo stomized children by pediatric pulmonologists.^Citation60

Vecellio L, Abdelrahim ME, Montharu J, Galle J, Diot P, Dubus JC. Disposable versus reusable jet nebulizers.^Citation122

Stegen K, Neujens A, Crombez G, Hermans D, van de woestijne KP, van den Bergh O. Negative effect of CO2 addition in nebulization.^Citation120

Caille V, Ehrmann S, Boissinot E, Perrotin D, Diot P, Dequin PF. Nasal additional oxygen delivery during air-driven jet nebulization increases FiO2.^Citation121

Britland S, Finter W, Chrystyn H, Eagland D, and Abdelrahim ME. Different aerosol formulations interact differently with the solutions and tissue in the respiratory system.^Citation139

Coates AL, Green M, Leung K, Chan J, Ribeiro N, Ratjen F, Charron M. Superiority of the investigational eFlow® by producing the same amount of aerosol in half time in comparison to PARI LC Plus®.^Citation123

Pitance L, Reychler G, Leal T, Reychler H, Liistro G, Montharu J, Lab T, Diot P, Vecellio L. Sidestream® jet nebulizer with and without corrugated piece of tubing.^Citation126

Wee WB, Leung K, Coates AL. A proposed aerosol evaluation model (i) mathematical model derivation, (ii) in vitro testing and (iii) in vivo testing.^Citation117

Tiemersma S, Minocchieri S, Lingen RA, Nelle M, Devadason SG. eFlow® nebulizer system more efficient in comparison to Intersurgical® Cirrus Jet® nebulizer and pressured meter dose inhaler with an Aerochamber® for drug delivery to preterm infants.^Citation124

Pitance L, vecellio L, Leal T, Reychler G, Reychler H, Liistro G. Sidestream® jet nebulizer with and without corrugated piece of tubing in six healthy spontaneous breathing volunteers.^Citation127

Rao N, Kadrichu N, Ament B. Refrigerating the impactor down to 5°C prior to aerosol measurement produced by vibrating mesh nebulizers.^Citation128

McCormack P, Southern KW, McNamara PS. Automatic data recording of patient adherence to aerosol administration.^Citation118

Skaria S, Smaldone GC. Omron NE U22 was evaluated in comparison to PARI LC Plus® and Sidestream®.^Citation129

Fadl A, Wang J, Zhang Z. Metered dose inhaler mouthpieces were modified in order reduce the inertial impaction in order to reduce aerosol deposition to the oral airway.^Citation130

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