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ATYPICAL TB ANTIBIOTIC RESEARCH ARTICLES


                         ~ ATYPICAL TB * MY STORY ~

  
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  Below are included some research articles from my Files.

* The Dates at the top indicate time of Recording the items in my Files
   Their Publication Dates are included at end of each article.
*  Colour highlights are also mine.

* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *












with these medications is not well tolerated by the elderly and relapse is common.
The two researchers treated 30 consecutive elderly HIV-negative individuals
(27 women and 3 men) with MAC lung disease with clarithromycin (500 mg bid)
or azithromycin (250 mg/d) on weekdays in combination with ethambutol
(15 mg/kg/d) and clofazimine (100 mg/d).
Four subjects withdrew from the study before sputum conversion due to
clarithromycin intolerance, while the remaining 26 completed an average
of 10 months of treatment.
According to the researchers, sputum findings converted to negative in all 26 patients (87%).
One patient died of unrelated causes during the study and 5 patients (19%) relapsed
an average of 17 months after completion of treatment.
Therefore, the combination of a macrolide, ethambutol, and clofazimine
was successful in 20 of 30 patients (67%),
they write.
This regimen, the University of Calgary researchers say,
was "relatively well tolerated and achieved sputum conversion to negative
and relapse rates that were at least as good  as any of the previously published
macrolide-containing regimens."
Moreover, this regimen "[spares] patients the need for treatment with
and potential side effects of rifamycins and aminoglycosides."
Chest 2003;124:1482-1486.





  

Moxifloxacin Has "Considerable" Promise as a New Anti-TB Agent

By Megan Rauscher
NEW YORK (Reuters Health) Dec 23 - Moxifloxacin has bactericidal activity comparable to rifampin in human subjects with pulmonary tuberculosis (TB), results of a phase II study indicate, leading researchers to recommend further testing of the drug.
"For some years there has been considerable excitement about the potential activity of this 8-methoxy quinolone, which had been shown to be highly active in vitro and in mouse models of TB," Dr. Stephen H. Gillespie from Royal Free and University College London told Reuters Health.
In the current trial, which was performed in collaboration with colleagues in Tanzania, patients were randomly allocated to 5 days of monotherapy with either moxifloxacin (400 mg/d), or isoniazid (300 mg/d), or rifampin (600 mg/d).
The estimated time to kill 50% of viable bacilli in sputum was 0.88, 0.46, and 0.71 days for moxifloxacin, isoniazid, and rifampin, respectively.
"Moxifloxacin had a similar level of activity to rifampicin, but less than isoniazid," Dr. Gillespie told Reuters Health.
After5 days of monotherapy, the patients then went on to conventional four-drug therapy with rifampin, isoniazid, pyrazinamide, and ethambutol.
This study "confirms that the excellent in vitro activity of moxifloxacin translates into activity in the human host," the researchers write in the December 1st American Journal of Respiratory and Critical Care Medicine.
"Moxifloxacin joins the small number of highly bactericidal antituberculosis drugs and may contribute to the development of more effective regimens," they add.
"Further large scale clinical trials should be performed to determine how best moxifloxacin should be used to improve the treatment of tuberculosis," Dr. Gillespie told Reuters Health.







 ( Tuesday, 26 May 2009 )


Research for (clofazimine-amikacin-R207910)

Research and comments
*Clarithromycin is the most active MAC antimicrobial agent and should be part of any drug regimen for treating active MAC disease in patients with or without AIDS.
*Similarly, azithromycin (600 mg once daily) was effective in reducing MAC bacteraemia.11 However, in a head-to-head comparison with clarithromycin, azithromycin was inferior (both drugs used in combination with ethambutol).12 Clofazimine should probably not be used at all to treat MAC as it has been associated with reduced survival.13

Warnings (http://www.medsafe.govt.nz/profs/datasheet/l/Lamprenecap.htm)

Clofazimine has an heterogeneous distribution throughout the body and a slow elimination rate, accumulating mainly in fatty tissue, reticuloendothelial system (macrophages, histiocytes and spleen) and skin. Adverse reactions to clofazimine are mainly linked to its uptake by tissue and organs. Because of this, the use of high doses for long periods should be avoided. Daily doses of greater than 100 mg Lamprene should be given for as short a time as possible (<3 months) and only under close medical supervision. After prolonged administration in high doses, clofazimine may accumulate in various organs, body fluids and tissues. Among the visceras, the jejunum has the highest drug depositions, closely followed by the spleen. The deposition of large amounts of clofazimine in the intestinal mucosa cause irritation, leading to gastrointestinal disturbances (e.g. abdominal pain (sometimes intermittent), nausea, vomiting and diarrhoea), usually with mild forms, but sometimes with more severe clinical manifestations. If crystals are deposited in the mesenteric lymph nodes and/or histiocytes at the lamina propria of the jejunal mucosa, this might lead to intestinal obstruction. If gastrointestinal symptoms develop during treatment, the dosage should be reduced or the interval between doses prolonged. Symptoms may slowly regress on withdrawal of the drug.
In the event of persistent diarrhoea or vomiting, the patient should be hospitalised.
bacterial load, MAC rapidly acquires resistance when treated with single drugs. Active disease therefore has to be treated with at least two drugs at all times. When a regimen is failing, at least two new drugs must be added or substituted. A salvage regimen is concocted from a limited armamentarium after a case-by-case evaluation. Amikacin or a quinolone (levofloxacin or ciprofloxacin), in addition to the first line drugs, may be considered.

Introduction
Amikacin sulfate (AMK) is a broad-spectrum and potent aminoglycoside with limited clinical use owing to a high dose requirement and renal and audio-vestibular apparatus toxicity.1-2 Major drawbacks associated with the use of earlier or conventional liposomal formulations are the tendency of liposomes to leak drug while in circulation, the extensive uptake of these liposomes by tissues of reticuloendothelial systems (RES), and the inability of liposomes to extravasate into infected tissue.3-4 Therefore, localized liposomal AMK delivery was considered for the treatment of cystic fibrosis infections in the lungs. Liposomal encapsulation of AMK will give the required release of drug for a longer time duration at the localized site, thereby reducing both the chances of systemic side effects and the frequency of dosing.
The use of amikacin for first-line therapy is limited, despite its excellent bactericidal activity against gram-negative organisms. Poor oral absorption, a short half-life, and serious renal, auditory, and vestibular toxicities necessitate frequent intravenous administration, with concomitant monitoring of drug levels to ensure that the levels in plasma remain within a narrow therapeutic window (26).

Amikacin (Medicine net.com)
HOW TO USE: This medication is given by injection. It may be injected into a large muscle such as the buttocks or infused into a vein over 30 minutes to one hour. It is usually given two or three times a day for 7 to 10 days. Antibiotics work best when the amount of medicine in your body is kept at a constant level. Do this by using the medication at evenly spaced intervals throughout the day and night as prescribed. Continue using this for the full time prescribed. Stopping the medication too soon may result in ineffective treatment.
SIDE EFFECTS: This medication may cause nausea, vomiting or weakness as your body adjusts to the medication. If these effects continue or become severe, inform your doctor. This medication can cause hearing loss or kidney damage especially if used in high doses or for prolonged periods of time. It is important the proper dose be used. The site where the injection is given may be red and irritated for a few days. Notify your doctor if the irritation continues or becomes worse. Notify your doctor immediately if you develop: dizziness, ringing in the ears, hearing loss, skin rash, difficulty breathing, difficult or painful urination, muscle twitching. If you notice other effects not listed above, contact your doctor or pharmacist.
NOTES: Laboratory tests and blood counts will be done routinely while using this to monitor its effects and prevent side effects.
Drugs.com

Renal side effects

One study has shown that hyperbilirubinemia in patients with biliary obstruction may also be a predisposing factor to aminoglycoside nephrotoxicity.

In one prospective, nonrandomized study, patients developed nephrotoxicity in 25% of amikacin courses.
Renal side effects have included nephrotoxicity (serum creatinine elevations, albuminuria, presence of red and white cells and casts in urine, azotemia, and oliguria) in 2% to 10% of patients. Predisposing factors include advanced age, preexisting renal insufficiency, dehydration, and concomitant use of other potentially nephrotoxic drugs.
Discolouration of the conjunctiva, cornea (eyes) and tears.
Macrolides
Clarithromycin, Azithromycin
Quinolones
Moxifloxacin,ciprofloxacin or levofloxacin
Aminoglycosides
Amikasin





New TB Drug May Shorten Treatment Times

NEW YORK (Reuters Health) Dec 09 /04- 
A new antibiotic specific to mycobacteria is expected to "dramatically improve TB control programs," according to a report published online December 9th in Science.
Dr. Koen Andries, of Johnson & Johnson Pharmaceutical Research and Development in Beerse, Belgium, and his multinational research team developed a series of compounds, diarylquinolines, which possess potent in vitro activity against several mycobacterial species.
The most active compound of the class, R207910, appears to have a novel target, inhibiting the proton pump of mycobacterial ATP synthase.
There is no concern about an interaction with human ATP synthase, Dr. Andries told Reuters Health during a teleconference, because "when we compare the gene sequence of mycobacterial ATP synthase with the ATP synthase of the human genome, they are quite different." And indeed, phase I trials in humans revealed no adverse effects during 2 weeks of treatment, he added.
Further studies showed that R207910 lacks cross-resistance with other currently used anti-TB agents. In fact, the authors note, 30 different isolates of multiple drug-resistant (MDR) TB strains and 10 fully susceptible strains were susceptible to 0.100 g/mL of R207910, concentrations readily achieved when administered to mice and humans.
The agent appears to be effective against all mycobacteria, including the human pathogens M. tuberculosis, M. kansasii, M. fortuitum, M. abscessus, and Mycobacterium avium complex (MAC).
"In the mouse model, our drug as a monotherapy is as active as the current standard of care, triple therapy with rifampin, isoniazid and pyrazinamide," Dr. Andries said. "Of course, our drug is not to be used as a monotherapy because that would inevitably lead to emergence of resistance, but it does demonstrate the high potency of the compound."
Perhaps even more importantly, "when we compared the results of R207910 combined with isoniazid and pyrazinamide with the standard of care, our combo achieved the same result after 1 month as that obtained after 2 months of standard of care combination therapy."
"We are optimistic that we will be able shorten treatment duration by about 50% based on these data," he added.
He also pointed out that the R207910 combination is compatible with HIV treatment combinations, whereas treatment that includes rifampin is associated with drug-drug interactions that increase the metabolism some HIV agents.
Science 2004.
www.sciencexpress.org/9 December 2004/Page 1/10.1126/science.1106753



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