The design and development of a multicentric protocol to investigate the impact of adjunctive doxycycline on the management of peripheral lymphoedema caused by lymphatic filariasis and podoconiosis.

BACKGROUND: As new lymphatic filariasis infections are eliminated through mass chemotherapy, previously affected individuals are left with the sequellae, especially chronic progressive lymphoedema. Currently this is managed by careful attention to limb hygiene to prevent infection. Studies over the past 15 years have suggested that the incorporation of doxycycline treatment may arrest or even reverse progression of lymphoedema. Most of this work has been observational or based on small studies, and if this intervention is effective, studies need to be conducted on a larger scale and under diverse geographical and social conditions before it can be incorporated into treatment policy. METHODS/DESIGN: The double-blind, placebo-controlled study was designed to investigate the impact of six weeks treatment with doxycycline added to standard limb hygiene on early stage filarial lymphoedema in five sites in Africa and the Indian subcontinent. One site in Cameroon is selected for studying lymphoedema in podoconiosis. Each site was individually powered with the potential to undertake a meta-analysis on completion. Evaluation methods followed those used in Ghana in 2012 with additions resulting from advances in technology. The details of the core protocol and how it was varied to take account of differing situations at each of the sites are provided. The study will enrol up to 1800 patients and will complete in mid-2021. CONCLUSIONS: This paper provides details of what challenges were faced during its development and discusses the issues and how they were resolved. In particular, the reasons for inclusion of new technology and the problems encountered with the supply of drugs for the studies are described in detail. By making these details available, it is hoped that the study protocol will help others interested in improving treatment for filarial lymphoedema in the design of future studies. Trial registration India: Clintrials.gov. NCT02929121 registered 10 Oct 2016: https://clinicaltrials.gov/ct2/show/NCT02929121 Mali: Clintrials.gov. NCT02927496 registered 7 Oct 2016: https://clinicaltrials.gov/ct2/show/NCT0292749 Sri Lanka: Clintrials.gov. NCT02929134 registered 10 Oct 2016: https://clinicaltrials.gov/ct2/show/NCT02929134 Ghana: ISRCTN. 14042737 registered 10 July 2017: https://doi.org/10.1186/ISRCTN14042737 Tanzania: ISRCTN. 65756724 registered 21 July 2017: https://doi.org/10.1186/ISRCTN65756724 Cameroon: ISRCTN. 1181662 registered 25 July 2017: https://doi.org/10.1186/ISRCTN11881662.

A Calculation Tool and Process to Pre-Position Pharmaceuticals for Anthrax Post-Exposure Prophylaxis.

Anthrax, caused by Bacillus anthracis, is considered a severe bioterrorism threat because of its high mortality rate. The Chicago Healthcare System Coalition for Preparedness and Response (CHSCPR) aims to pre-position antibiotic medical countermeasures (MCMs) at healthcare facilities in order to provide on-site anthrax post-exposure prophylaxis. Pharmacists proposed moving toward a new process that involved the development of a standardized calculation methodology for acquiring supply drugs. This was an interventional quality improvement project aimed at optimizing inventory, acquisition, and distribution of antibiotic MCMs for anthrax post-exposure prophylaxis at Chicago hospitals for hospital personnel, associated first responders, and their families. The primary goal of the project was to pre-position a sufficient quantity of pharmaceuticals to allow Chicago hospitals to function as closed points of dispensing (PODs) for 72 hours; a secondary goal was to provide a 96-hour supply of anthrax post-exposure prophylaxis. A total of 35 Chicago hospitals were invited to participate in this intervention study, and 30 hospitals agreed to participate. Based on our calculation tool, we initially identified 6 (20%) hospitals with adequate oral doxycycline and ciprofloxacin inventory to last 72 hours and 3 (10%) hospitals with inventory to last 96 hours as a closed POD for anthrax post-exposure prophylaxis. The necessary quantities of medication needed to establish 72 and 96 hours of anthrax post-exposure prophylaxis were calculated by the CHSCPR and negotiated with a drug wholesaler to obtain product with maximum shelf-life and discounted pricing. Acting as a group purchaser, the CHSCPR organized drop shipment of medication directly to facilities from a wholesaler. This systematically calculated, pre-deployed pharmaceutical cache enhanced availability of antibiotic MCMs for anthrax post-exposure prophylaxis in 30 Chicago hospitals, allowing them to function as closed PODs for 96 hours during an incident.

[Doxycycline]. / Doxycycline.

Doxycyclin is a semi-synthetic structural isomer of the tetracycline family. It exhibits good intra-cellular penetration, with bacteriostatic activity on many bacteria. Different types or bacterial resistance are known. Acquired resistance has a ribosomal or a plasmidic mechanism. Resistance of Propionibacterium acnes is secondary to a mutation of ARNr. Doxycyclin also has an anti-inflammatory activity, via numerous pathways. Doxycyclin is rapidly and almost completely absorbed by the digestive tract. Food has no incidence on the absorption. It has a high but labile affinity for proteins with 90 p. 100 of the molecule linked. It rapidly diffuses in the extravascular compartment and in most of the tissues. Bile excretion is the main excretion route. It occurs more slowly by the kidney with tubular reabsorption. The main dermatological indication is acne with daily dose varing between 50 mg and 100 mg. Although good assays are lacking, a large professional consensus has validated its use. It is also active at the same dosage in rosacea. Chlamydial and mycoplasma urethritis may be treated by doxycyclin, and this antibiotic is presently used as second choice. Many other diseases may be treated as a primary or secondary choice, such as treponematoses, brucellosis, pasteurellosis, borreliosis, rickettsioses and cholera. Some non infectious diseases have been occasionally treated by doxycycline. Digestive side effects are the more frequent. Esophageal toxicity has been reduced with tablets and sufficient concomitant water ingestion. Phototoxicity is dose-dependent. Various cutaneous side effects have been described, some of them severe. Systemic toxicity is rare. Pregnancy is a contra-indication, and as other tetracyclines, it should not be given to children and during lactation. Doxycycline is commercialized as tablets. No reduction of the dose is necessary in renal failure. Association with retinoids is not recommended. Anticoagulants are potentialized. Didanosin, iron, and mineral salts lower its activity.