Inhaled antibiotic therapy using dry-powder microparticles is an attractive means of drug delivery to the diseased airway. Compared with nebulization, dry-powder inhalation is faster, requires minimal equipment, and is less likely to disperse the drug into ambient air. Inhaled encapsulated drugs may avoid most of the toxicities associated with their systemically-administered counterparts. These factors are likely to improve compliance, overall microbiologic success, and patient outcomes.
In our study, ceftazidime and ciprofloxacin were co-encapsulated into the DAL-based microparticles using the simple method described here (Fig. ). This dry powder system is advantageous as compared to a nebulizer for co-delivery of the two antibiotics, as the two tend to precipitate when they co-exist in solution (13
The microparticles containing each antibiotic (CTZ and CIP microparticles) displayed different aerodynamic properties: adding ceftazidime decreased the microparticles’ FPF, whereas adding ciprofloxacin increased it. Moreover, ceftazidime and ciprofloxacin at all degrees of loading had different ACI deposition profiles, so separate administration of CTZ or CIP microparticles in vivo would not guarantee co-deposition, the lack of which may accelerate the development of antibiotic resistance. Although there were substantial areas of overlap between the ACI deposition profiles of the microparticles containing each drug alone, this could easily not be the case with other compounds. This potential problem would be obviated by co-encapsulation. Co-encapsulation also improved the microparticles’ aerodynamic properties and FPF as compared to the microparticles containing equivalent amount of ceftazidime alone; hence in vivo the particles co-encapsulating the two antibiotics will have a higher probability of deep airway deposition. These considerations suggest that co-encapsulation of antibiotics may be clinically warranted.
All the microparticles containing antibiotics showed antibacterial activity, allaying concerns about negative effects of spray-drying on the stability of the drugs. The co-encapsulation described here achieved additivity in antibiotic effectiveness; however, the potency of such particles could be vastly enhanced if the drugs were synergistic. This could reduce the mass of powder to be inhaled and/or require a lower proportion of active payload per particle, which could be beneficial if the drug adversely affected the aerodynamics. Co-encapsulation of compounds that enhance each other’s performance has been used effectively in other settings (27
Although the ACI is a widely-accepted in-vitro
model of pulmonary deposition of particulate matter, the results it provides may not be totally predictive of in-vivo
). In the airways of patients with CF and some other conditions, P. aeruginosa
exists in a biofilm containing mucins and various products of neutrophil breakdown (2
), which entrap it within tenacious mucus. Unless there is a mucolytic effect of a component of the formulation (which we have not demonstrated), microparticulate delivery systems are unlikely to enhance flux through the mucus.
Importantly, a potential impediment to the delivery of antibiotics by microparticulate systems is the low potency of the compounds, necessitating the delivery of large quantities of material. In preclinical studies, gentamicin doses of 160–180 mg (micronized into dry powder) (31
) and tobramycin doses of 13 mg (as 25 mg of PulmoSphere® particles) (33
) have been used in healthy volunteers and those affected with CF; 20 mg doses of particulate ciprofloxacin, doxycycline, or co-spray-dried ciprofloxacin–doxycycline were used in a recently-reported formulation study (34
). Anti-P. aeruginosa
of gentamicin is 5 μg/ml (35
), that of ciprofloxacin is less than 0.5 μg/ml (36
), and that of ceftazidime is 2 μg/ml (37
). One may therefore extrapolate that to achieve anti-P. aeruginosa
effects approximately equal to those of 160 mg of gentamicin administered as DPI (32 times the MIC90
) would require approximately 16 mg of ciprofloxacin or 64 mg of ceftazidime. Since from our data the ceftazidime and ciprofloxacin are at least additive against P. aeruginosa
, their individual doses may be halved without loss of total activity if the drugs are co-administered in a single particle. Hence, only approximately 40 mg of drugs (8 mg of ciprofloxacin and 32 mg of ceftazidime) plus the requisite excipient mass would have to be inhaled to achieve the effect of 160 mg of gentamicin, while providing clinically advantageous double coverage. Preclinical studies will be necessary to determine whether sufficient doses of antibiotics can be delivered by an amount of particles that is practical.