What influences the implementation and sustainability of antibiotic stewardship programmes in hospitals? A qualitative study of antibiotic pharmacists' perspectives across South West England.

OBJECTIVES: Antibiotic stewardship programmes (ASPs) are needed at every hospital as they can improve antibiotic use and address antibiotic resistance. Pharmacists are key agents and specialists in these programmes. This study explored antibiotic pharmacists' perceptions of factors that influence the implementation and sustainability of hospital-based ASPs. METHODS: Semistructured interviews were conducted with hospital antibiotic pharmacists face-to-face or by telephone. NVivo V.12 software was used to collate and organise the data grouped within codes. Thematic analysis was undertaken using inductive and deductive approaches to produce overarching themes. RESULTS: Thirteen pharmacists from 13 hospitals were interviewed. Four main themes were identified: (1) 'organisational culture' which highlighted the importance of strong local clinical leadership to help achieve organisational buy-in and address resistance among physicians or clinical hierarchies; (2) 'national influences' including networks, guidance and incentive schemes which were considered to be a driver to bring about changes across organisation; (3) 'continuous monitoring with feedback ASP data, preferably through direct communication' to demonstrate the impact of the programmes which then facilitated ongoing support from local leadership and improved engagement across organisation; and (4) 'resources' which indicated the need of information technology and dedicated personnel with protected time to support ASP activities. CONCLUSIONS: Interventions and strategies should operate at different levels-individual, team, organisational and national-to help implement and sustain ASPs in hospital. This is also the first study to identify and highlight the importance of national initiatives in contributing to the implementation and sustainability of hospital-based ASPs.

Targeted delivery of lopinavir to HIV reservoirs in the mesenteric lymphatic system by lipophilic ester prodrug approach.

The combined antiretroviral therapy (cART) can efficiently suppress HIV replication, but the cessation of cART usually results in viral rebound, mostly due to the presence of viral reservoirs. The mesenteric lymphatic system, including mesenteric lymph nodes (MLNs), is an important viral reservoir into which antiretroviral drugs poorly penetrate. In this work, we proposed a novel lipophilic ester prodrug approach, combined with oral lipid-based formulation, to efficiently deliver lopinavir (LPV) to the mesenteric lymph and MLNs. A series of prodrugs was designed using an in-silico model for prediction of affinity to chylomicrons (CMs), and then synthesized. The potential for mesenteric lymphatic targeting and bioconversion to LPV in physiologically relevant media was assessed in vitro and ex vivo. Subsequently, LPV and selected prodrug candidates were evaluated for their in vivo pharmacokinetics and biodistribution in rats. Oral co-administration of lipids alone could not facilitate the delivery of unmodified LPV to the mesenteric lymphatic system and resulted in undetectable levels of LPV in these tissues. However, a combination of the lipophilic prodrug approach with lipid-based formulation resulted in efficient targeting of LPV to HIV reservoirs in mesenteric lymph and MLNs. The maximum levels of LPV in mesenteric lymph were 1.6- and 16.9-fold higher than protein binding-adjusted IC90 (PA-IC90) of LPV for HIV-1 (140 ng/mL) following oral administration of simple alkyl ester prodrug and activated ester prodrug, respectively. Moreover, the concentrations of LPV in MLNs were 1.1- and 7.2-fold higher than PA-IC90 following administration of simple alkyl ester prodrug and activated ester prodrug, respectively. Furthermore, the bioavailability of LPV was also substantially increased following oral administration of activated ester prodrug compared to unmodified LPV. This approach, especially if can be translated to other antiretroviral drugs, has potential for reducing the size of HIV reservoirs within the mesenteric lymphatic system.

A prospective, randomized, double dummy, placebo-controlled trial of oral cefditoren pivoxil 400mg once daily as switch therapy after intravenous ceftriaxone in the treatment of acute pyelonephritis.

OBJECTIVES: To compare the clinical and bacteriological effectiveness of intravenous (IV) ceftriaxone followed by oral cefditoren pivoxil or IV ceftriaxone for acute pyelonephritis. METHODS: A prospective randomized controlled trial of patients with a presumptive diagnosis of acute pyelonephritis was performed. Daily 2g IV ceftriaxone was initially given to all patients. After day 3, patients who satisfied the criteria for switch therapy were randomized to either group A (IV ceftriaxone) or group B (oral cefditoren pivoxil 400mg once daily). RESULTS: Eighty-two patients were enrolled; 41 (50%) patients in group A and 41 (50%) patients in group B were evaluated. There was no statistically significant difference in baseline characteristics between the two groups. Clinical cure was observed in 39 of 41 (95.1%) patients in group A and 41 of 41 (100%) patients in group B (p=0.15, 95% confidence interval (CI) -0.12 to 0.02). Urine bacteriological eradication was found in 63.4% in group A and 60% in group B (p=0.75, 95% CI -0.18 to 0.25). There was no statistically significant difference in adverse effects between the two treatment groups. CONCLUSION: These data suggest that IV ceftriaxone followed by oral cefditoren pivoxil is highly effective and well-tolerated for the treatment of acute pyelonephritis, even for uropathogens with a high proportion of quinolone-resistant strains.