Empirical treatment of community-acquired pneumonia and the development of fluoroquinolone-resistant tuberculosis.

UNLABELLED: BACKGROUND" Fluoroquinolone (FLQ) antibiotics are not uncommonly prescribed for community-acquired pneumonia that is later proven to be pulmonary tuberculosis (TB). Such FLQ monotherapy may result in FLQ-resistant pulmonary TB. METHODS: To assess outpatient FLQ use by patients with culture-proven pulmonary TB before diagnosis, TB registries in Alberta and Saskatchewan, Canada, were linked with provincial and federal drug benefit plans. To assess FLQ resistance, a case-control study was performed. RESULTS: Of 428 patients with pulmonary TB who were covered by a drug benefit plan, 74 (17.3%) had received > or = 1 FLQ prescription during the 6 months immediately before receipt of the diagnosis. Older patients (age, >64 years) were more likely than younger patients (age, 15-64 years) to be prescribed an FLQ (P < .05). Patients who were prescribed an FLQ received a total of 103 prescriptions. Most (54 [73.0%] of 74) patients who were prescribed an FLQ received a single prescription. Most (69 [67.0%] of 103) FLQ prescriptions were written within 90 days before the diagnosis of pulmonary TB. Patients who were prescribed an FLQ were not statistically significantly more likely than matched patients who were not prescribed an FLQ (control subjects) to be infected with FLQ-resistant Mycobacterium tuberculosis. Of 148 isolates of M. tuberculosis from patients and control subjects, 3 were FLQ resistant; all of these isolates were from patients who had received multiple FLQ prescriptions. Patients who had received multiple FLQ prescriptions were more likely than patients who had received a single FLQ prescription to be infected with FLQ-resistant M. tuberculosis (15.0% vs. 0.0%; odds ratio, 11.4; P = .04). CONCLUSIONS: Outpatient FLQ use, ostensibly for community-acquired pneumonia, is not uncommon among patients with pulmonary TB, especially older patients. Single FLQ prescriptions were not associated with FLQ-resistant M. tuberculosis, whereas multiple FLQ prescriptions were associated with FLQ resistance.

Hydroxyzine from topical phospholipid liposomal formulations: evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model.

Hydroxyzine, an effective but sedating H1-antihistamine is given orally to treat allergic skin disorders. This study was performed to assess the peripheral H(1)-antihistaminic activity and extent of systemic absorption of hydroxyzine from liposomes applied to the skin. Using L-alpha-phosphatidylcholine (PC), small unilamellar vesicles (SUVs) and multilamellar vesicles (MLVs) containing hydroxyzine were prepared. Hydroxyzine in Glaxal Base (GB) was used as the control. Using a randomized, crossover design, each formulation, containing 10 mg of hydroxyzine, was applied to the shaved backs of 6 rabbits (3.08 +/- 0.05 kg). Histamine-induced wheal tests and blood sampling were performed at designated time intervals up to 24 hours. Compared with baseline, hydroxyzine from all formulations significantly suppressed histamine-induced wheal formation by 75% to 95% for up to 24 hours. Mean maximum suppression, 85% to 94%, occurred from 2 to 6 hours, with no differences among the formulations. The areas of plasma hydroxyzine concentration versus time area under the curve (AUCs) from PC-SUV and PC-MLV, 80.1 +/- 20.8 and 78.4 +/- 33.9 ng/mL/h, respectively, were lower than that from GB, 492 +/- 141 ng/mL/h (P < or =.05) over 24 hours. Plasma concentrations of cetirizine arising in-vivo as the active metabolite of hydroxyzine, from PC-SUV, PC-MLV, and GB, were similar with AUCs of 765 +/- 50, 1035 +/- 202, and 957 +/- 227 ng/mL/h, respectively (P < or =.05). Only 0.02% to 0.06% of the initial hydroxyzine dose remained on the skin after 24 hours. In this model, hydroxyzine from SUV and MLV had excellent topical H1-antihistaminic activity, and minimal systemic exposure occurred. Cetirizine formed in-vivo contributed to some of H1-antihistaminic activity.

Hydroxyzine- and cetirizine-loaded liposomes: effect of duration of thin film hydration, freeze-thawing, and changing buffer pH on encapsulation and stability.

PURPOSE: To assess the effect of the duration of film hydration, freeze-thawing, and changing buffer pH on the extent of entrapment of hydroxyzine and cetirizine, H1-antihistamines with different polarity, into liposomes, and the stability of these liposomes. METHODS: Multilamellar vesicles (MLV) were prepared by thin-lipid film hydration using L-alpha-phosphatidylcholine (PC) and buffer containing 80 mg hydroxyzine at pH 7. For MLV containing hydroxyzine, the liposomes were subjected to 1) hydration for 1 h, 24 h, or 48 h for the control batch, batch B, or batch D respectively; and 2) hydration for 1 h, 24 h, or 48 h with freeze-thawing for 5-cycles for batch A, batch C, or batch E, respectively. These formulations were stored at 10 +/- 2 degrees C and 37 +/- 0.1 degrees C. Small unilamellar vesicles (SUV) and MLV were prepared using L-alpha-phosphatidylcholine (PC), and buffer at pH 5.0, 5.5, 6.0, 6.5, and 7.0, containing 80 mg hydroxyzine or 82 mg cetirizine by the ethanol injection and thin-lipid film hydration methods, respectively. These formulations were stored at 10 +/- 2 degrees C. Liposomes were evaluated immediately after preparation and after storage by determining percent entrapment of hydroxyzine (PETH) or of cetirizine (PEC) and by observing changes in the physical appearance (PA). Particle size (PSA) of the liposomes freshly prepared at pH=6.5 was measured from transmission electron micrographs (TEM). RESULTS: Increasing thin-film hydration time or repeated freeze-thawing did not affect the initial PETH or long-term stability of control, A, B, C, D, and E batches of MLV containing hydroxyzine stored at 10 +/- 2 degrees C. At 37 +/- 0.1 degrees C, PETH of all MLV batches decreased considerably after 1 month. This was more evident in batches B, C, and E exposed to freeze-thawing. The PETH of SUV increased markedly from 53.0% to 84.0% when the pH of the buffer was increased from 5.0 to 5.5. As pH increased from 6.0 to 7.0, PETH continued to increase from 84% to 94%. The initial PETH of MLV increased slightly from 82.0% to 94.0% as the buffer pH values increased from 5.0 to 7.0. There was no effect of pH on initial PEC, and stability of SUV or initial PEC of MLV, which ranged from 92% to 94%, as buffer pH values increased from 5.0 to 6.5. After storage at 10 +/- 2 degrees C PEC in MLV decreased from 94% to 74%. CONCLUSIONS: The freeze-thawing processes had some effect on the stability of liposomes stored at temperatures higher than ambient temperature, 37 +/- 0.1 degrees C. The effect of changing the buffer pH from 5.5 to 7.0, and from 5.0 to 6.5 on initial PETH and PEC, respectively, was minimal. After 24 months at l0 +/- 2 degrees C, pH had no effects on PETH; however, PEC of MLV decreased.

Cetirizine from topical phosphatidylcholine liposomes: evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model.

This study was performed to assess the peripheral H(1)-antihistaminic activity and extent of systemic absorption of cetirizine from liposomes applied to the skin. Cetirizine was incorporated into small unilamellar vesicles (SUV) and multilamellar vesicles (MLV) prepared using L-alpha-phosphatidylcholine, and into Glaxal Base (GB), used as the control. In a randomized, cross-over study, each formulation, containing 10 mg of cetirizine, was applied to depilated areas on the backs of six rabbits (3.08+/-0.05 kg). Histamine-induced wheal tests and blood sampling were performed before cetirizine application and at designated times for up to 24 h. Compared with the baseline, histamine-induced wheal formation was suppressed by cetirizine in SUV and MLV from 0.5-24 h and by cetirizine in GB from 0.5-8 h, p

Cetirizine from topical phosphatidylcholine-hydrogenated liposomes: evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model.

Cetirizine, an effective, minimally sedating, second-generation H1-antihistamine is widely used orally to treat allergic skin disorders. This study was performed to assess the peripheral H1-antihistaminic activity and extent of systemic absorption of cetirizine from liposomes applied to the skin. Cetirizine was incorporated into small unilamellar vesicles (SUV) and multilamellar vesicles (MLV) prepared using L-alpha-phosphatidylcholine hydrogenated (HPC), and into Glaxal Base (GB) as the control. In a randomized, crossover study, each formulation, containing 10 mg of cetirizine, was applied to the depilated backs of 6 rabbits (3.08 +/- 0.05 kg). Histamine-induced wheal tests and blood sampling were performed before cetirizine application and at designated times for up to 24 hours afterwards. Compared with baseline, histamine-induced wheal formation was suppressed by cetirizine in SUV only at 24 hours, in MLV from 0.5 to 24 hours, and in GB from 0.5 to 8 hours (P < or = .05). Wheal suppression by cetirizine in SUV at 24 hours (91.7% +/- 5.2%) and in MLV from 1 to 24 hours (93.8% +/- 2.2% to 76.2% +/- 6.5%) was greater than in GB (36.5% +/- 7.4% to 60.6% +/- 14.2%) from 1 to 24 hours (P < or = .05). Faster onset, as well as greater and more persistent suppression was obtained from cetirizine in MLV. Plasma cetirizine concentrations from MLV (area under the curve [AUC] of 221.2 +/- 42.3 ng x hr/mL) were lower than from GB (AUC of 248.3 +/- 34.6 ng.hr/mL). In this model, cetirizine from MLV had excellent topical H(1)-antihistamine activity, while systemic exposure was reduced, compared with cetirizine from GB.