Aerosol antibiotics: considerations in pharmacological and clinical evaluation.

Aerosol antibiotics: considerations in pharmacological and clinical evaluation.

Curr Opin Biotechnol. 2008 Nov 24.

Dudley MN, Loutit J, Griffith DC.
Mpex Pharmaceuticals, San Diego, CA 92121, United States.

Increasing antibiotic resistance and lack of R&D productivity of new classes of antimicrobial agents directed against Gram-negative bacteria necessitate new approaches to maximize the efficacy of existing classes of drugs. Direct administration of drugs to the lung via the inhalational route provides for high concentrations at the target site of action in patients with pulmonary infections. The efficacy of aerosol antibiotic administration has been best demonstrated with aerosolized tobramycin in the management of chronic infections because of Pseudomonas aeruginosa in cystic fibrosis (CF) patients. Unfortunately, inconvenient regimens leading to poor patient adherence to therapy, and the increasing frequency of multidrug-resistant strains have necessitated the search for additional agents. Integration of aerosol science, PK-PD and clinical trial designs are important for the development and evaluation of these new aerosol agents in both chronic infections (e.g. CF and chronic obstructive pulmonary disease (COPD)) as well as acute infections (e.g. bacterial pneumonias).

This review outlines important considerations and recent progress in this emerging area.

PubMed

Zymar (Gatifloxacin 0.3%) Shows Excellent Gram-Negative Activity Against Serratia marcescens and Pseudomonas aeruginosa

Zymar (Gatifloxacin 0.3%) Shows Excellent Gram-Negative Activity Against Serratia marcescens and Pseudomonas aeruginosa in a New Zealand White Rabbit Keratitis Model.

Cornea. 2007 Jun

Mah FS,
Romanowski EG,
Kowalski RP,
Yates KA,
Gordon YJ.

From the Charles T. Campbell Ophthalmic Microbiology Laboratory, UPMC Eye Center, Ophthalmology and Visual Sciences Research Center, Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

PURPOSE: Whereas gatifloxacin, a newer fluoroquinolone, was engineered to increase its Gram-positive potency, we assessed whether it still retained significant Gram-negative activity in vivo. Specifically, we compared the efficacy of Zymar (gatifloxacin 0.3%), Ciloxan (ciprofloxacin 0.3%), and fortified tobramycin (14 mg/mL) in the treatment of experimental Gram-negative bacterial infections of Serratia marcescens (SM) and Pseudomonas aeruginosa (PA) in the New Zealand White (NZW) rabbit keratitis model.

METHODS: A total of 30 NZW rabbits each were intrastromally inoculated in both eyes with approximately 1000 CFU of SM and PA. By E-test, the minimum inhibitory concentrations (MICs; mug/mL) for SM were gatifloxacin (0.125), ciprofloxacin (0.047), and tobramycin (1.5), and for PA were gatifloxacin (0.125), ciprofloxacin (0.19), and tobramycin (0.5). After 16 hours, the rabbits were divided into 4 treatment groups: (1) Zymar, (2) Ciloxan, (3) fortified tobramycin, and (4) saline control. One drop was instilled in both eyes every 15 minutes for 5 doses and then every 30 minutes for 14 doses. One hour after the final treatment, the animals were euthanized, and bacterial colony counts from the corneas were determined.

RESULTS: For SM, Zymar and Ciloxan significantly reduced the colony counts compared with tobramycin and saline control. Zymar was more effective than Ciloxan.For PA, all antibiotics reduced equivalently the colony counts compared with the saline control

CONCLUSIONS: The enhanced Gram-positive activity of gatifloxacin is not associated with any decreased Gram-negative activity in vivo. Zymar may prove useful for SM and PA keratitis.

PMID: 17525656 [PubMed - in process]

Colistin is Effective in the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections in Cancer Patients.

Colistin is Effective in the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections in Cancer Patients.
Antimicrob Agents Chemother. 2007 Mar 26

Hachem RY,
Chemaly RF,
Ahmar CA,
Jiang Y,
Boktour MR,
Rjaili GA,
Bodey GP,
Raad II.
The University of Texas M. D. Anderson Cancer Center, Department of Infectious Diseases, Houston, Texas, and Staten Island University Hospital, Staten Island, New York.

Background: The increasing incidence of infections caused by multidrug-resistant Pseudomonas aeruginosa is a worldwide health problem. Because no new anti-pseudomonal agents are expected to be available in the near future, we evaluated the safety and efficacy of colistin, an old drug with bactericidal activity against this organism.

Methods: We collected clinical and demographic data on 95 cancer patients diagnosed with multidrug-resistant P. aeruginosa between January 2001 and January 2004 and treated with either colistin (colistin group) or at least one active anti-pseudomonal agent (a beta-lactam antibiotic or quinolone) (control group). We compared both groups.

Results: Thirty-one patients had been treated with colistin and 64 had been treated with an anti-pseudomonal non-colistin-containing regimen. Compared with the control group, patients in the colistin group had lower median age (52 vs 62 years; P = 0.012), but more likely to have had nosocomial infections (87% vs 64%; P = 0.02). Twenty-five patients (81%) in the colistin group and 40 patients (63%) in the control group had an APACHE II score of >15 (P = 0.074). Overall clinical response rate was 52% in the colistin group versus 31% in the non-colistin group (P = 0.055). Multiple logistic regression analysis showed that those patients treated with colistin were 2.9 times (95% CI: 1.1 to 7.6) more likely to experience a clinical response to therapy than were those in the control group (P = 0.026).

Conclusions: Colistin therapy was at least as effective and as safe as beta-lactam antibiotics and quinolones in the treatment of multidrug-resistant P. aeruginosa infections and, hence, may be a useful or preferred alternative therapy for this infection in cancer patients.

Antimicrobial Agents and Chemotherapy Online