Minocycline for short-term neuroprotection.

Elewa HF, Hilali H, Hess DC, Machado LS, Fagan SC.1

Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Athens, Georgia; Specialty Care Service Line, Veterans Administration Medical Center, Augusta, Georgia.

April 2006

Minocycline is a widely used tetracycline antibiotic. For decades, it has been used to treat various gram-positive and gram-negative infections. Minocycline was recently shown to have neuroprotective properties in animal models of acute neurologic injury. As a neuroprotective agent, the drug appears more effective than other treatment options. In addition to its high penetration of the blood-brain barrier, minocycline is a safe compound commonly used to treat chronic infections. Its several mechanisms of action in neuroprotection-antiinflammatory and antiapoptotic effects, and protease inhibition-make it a desirable candidate as therapy for acute neurologic injury, such as ischemic stroke. Minocycline is ready for clinical trials of acute neurologic injury.

Pharmacotherapy

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Related Article:

The potential of minocycline for neuroprotection in human neurologic disease.

The potential of minocycline for neuroprotection in human neurologic disease.Zemke D, Majid A.Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824, USA.

Minocycline is a member of the tetracycline class of molecules with broad-spectrum antibiotic activity. The unique properties of minocycline result in increased tissue distribution when compared with the other tetracyclines. Of particular interest is the ability of minocycline to diffuse into the central nervous system at clinically effective levels. Aside from its antimicrobial properties, minocycline has been found to have beneficial effects on inflammation, microglial activation, matrix metalloproteinases, nitric oxide production, and apoptotic cell death. Concordantly, minocycline has been found to have neuroprotective effects in animal models of a number of diseases including stroke, multiple sclerosis, and Parkinson disease. The proven safety of minocycline over decades of use as an antibiotic suggests that it may have potential for development into an effective treatment of multiple neurologic conditions in humans.

Publication Types:

Review

PMID: 15613934 [PubMed - indexed for MEDLINE]

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Minocycline

HOW TO USE:

Take minocycline tablets or capsules by mouth. Follow the directions on the prescription label. Swallow tablets or capsules whole with a full glass of water; take tablets or capsules in an upright or sitting position. Taking a sip of water first, before taking the tablets or capsules, may help you swallow them. If possible take bedtime doses at least 10 minutes before lying down. It is best to take minocycline without food, but if it upsets your stomach take it with food. Take your doses at regular intervals. Do not take your medicine more often than directed. Finish the full course prescribed by your prescriber or health care professional even if you think your condition is better. Do not stop taking except on your prescriber's advice.
Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.

SIDE EFFECTS:

Side effects that you should report to your prescriber or health care professional as soon as possible: dark yellow or brown urine; difficulty breathing; fever; headache; increased sensitivity to the sun or ultraviolet light; itching in the rectal or genital area; pain on swallowing; redness, blistering, peeling or loosening of the skin, including inside the mouth; stomach pain or cramps; skin rash or itching; unusual bleeding or bruising; unusual tiredness or weakness; yellowing of eyes or skin.

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome): diarrhea; discolored tongue or teeth; drowsiness, dizziness; loss of appetite; nausea, vomiting; sore mouth.

PRECAUTIONS:

Tell your prescriber or health care professional if your symptoms do not improve in 3 to 5 days. Sometimes it will take longer than this before you get better.

Do not take minocycline just before going to bed. It may not dissolve properly when you are lying down and can cause ulceration of your food pipe.

Keep out of the sun, or wear protective clothing outdoors and use a sunscreen. Do not use sun lamps or sun tanning beds or booths.

Birth control pills (contraceptive pills) may not work properly while you are taking this medicine. Use an extra method of birth control for at least one month.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how minocycline affects you. To reduce the risk of dizzy or fainting spells, do not sit or stand up quickly, especially if you are an older patient.

If you are being treated for a sexually transmitted disease, avoid sexual contact until you have finished your treatment. Your sexual partner may also need treatment.

If you are going to have surgery, tell your prescriber or health care professional that you are taking minocycline.

Antacid can stop minocycline working. If you get an upset stomach and want to take an antacid, make sure there is an interval of at least 2 hours since you last took minocycline, or 4 hours before your next dose.

Never take minocycline if it is past the expiration date; it can make you seriously ill.

DRUG INTERACTIONS:

Antacids; calcium salts; cholestyramine; colestipol; digoxin; female hormones, including contraceptive or birth control pills; ferrous sulfate; magnesium salts; other antibiotics; phenytoin; sodium bicarbonate; warfarin.

Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.

NOTES:

Prescriber needs to know if you have any of these conditions: kidney disease; liver disease; long exposure to sunlight (working outdoors); an unusual or allergic reaction to minocycline, other tetracyclines; pregnant or trying to get pregnant; breast-feeding.

MISSED DOSE:

f you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses. There should be an interval of at least 4 to 6 hours between doses.

STORAGE:

Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15-30 degrees C (59-86 degrees F). Protect from light and moisture. Throw away any unused medicine after the expiration date.

Allergy to cloxacillin with normal tolerance to amoxicillin and cefuroxime

Case Reports - Antibiotic Allergy

J Domínguez-Ortegaa JC Martínez-Alonsob MC Marcos-Pérezc C Kindelanc A Fradesd aUnit of Allergy. Hospital Universitario de Getafe. Madrid. Spain.bUnit of Allergy. Hospital Virgen de la Concha. Zamora. Spain.cUnit of Allergy. Hospital Universitario de Getafe. Madrid. Spain.dUnit of Allergy. Hospital Virgen de la Concha. Zamora. Spain

Abstract

Background: Cloxacillin is a semisynthetic penicillin widely used in nonmethicillin resistant Staphylococcus aureus infections. Several hypersensitivity reactions to cloxacillin have been reported, although IgE-mediated allergic reactions to the drug are rare and there is little information about possible tolerance to other semisynthetic penicillins or cephalosporins in patients with cloxacillin allergy. We present 2 patients with demonstrated IgE-mediated allergy to cloxacillin and tolerance to amoxicillin and cefuroxime.

Case reports: Case 1. A 47-year-old woman began treatment with cloxacillin due to acute cellulitis. After ingesting 500 mg of the drug, she experience generalized maculopapular eruption and facial angioedema. Case 2. A 55-year-old woman presented an episode of acute urticaria and labial angioedema 60 minutes after ingesting 500 mg of cloxacillin for a skin abscess.

Methods and results: Skin prick tests were positive to cloxacillin in case 1 and negative in case 2. However, an intradermal test was positive to cloxacillin (2 mg/ml) in case 2. Simple-blind oral challenge tests with amoxicillin (1 g) and cefuroxime (500 mg) were well-tolerated by both patients.

Conclusions: We present 2 patients allergic to cloxacillin with normal tolerance to other betalactam antibiotics, confirming that cross-reactivity among these antibiotics seems to be uncommon. Complete allergy study, including an oral challenge test, should be considered in these patients.

INTRODUCTION

Cloxacillin is a semisynthetic penicillinase-resistant penicillin widely used in non-methicillin resistant Staphylococcus aureus infections. Most frequent side effects of cloxacillin are gastro-intestinal manifestations like vomiting or diarrea, although there have been reported different hypersensitivity reactions 1,2 . However, IgE-mediated allergic reactions to the drug are rare and there is little previously reported information about the management of allergic patients to cloxacillin in order to demonstrate tolerance to other semi-synthetic penicillins or cephalosporins 3 . We present two different patients with demonstrated IgE-mediated allergy to cloxacillin with normal tolerance to amoxicillin and cefuroxime.

CASE REPORT

Case 1. A 47-year-old woman diagnosed of chronic lymphedema after a radical mastectomy, began treatment with cloxacillin due to an acute cellulitis. Shortly after the intake of Orbenin® 500 mg (Glaxo-SmithKline-Beecham,Toledo.Spain) she experience generalized pruritic maculo-papular eruption, hives and angioedema of the face.

Case 2. A 55-year-old woman, with a personal background of smoking, who had taken cloxacillin 500 mg for an abscess involving the bulbous end of a finger. 60 minutes after the intake of the first pill, she presented an episode of acute urticaria and labial angioedema. Both patients were completely recovered after the administration of parenteral treatment (40 mg of 6-methyl-prednisolone and intravenous dyphenhydramine). They both had previously taken cloxacillin without any reaction and they had not eaten any food or had not being doing exercise in the previous 4 hours.

ALLERGIC STUDY

In the Allergy Unit at our Hospital, Skin prick tests (SPT) with benzylpenicillin (10.000 U/ml), mayor and minor determinants mixture of benzylpenicillin (BPO and MDM. Diater. Madrid. Spain), cloxacillin (20 mg/ml), amoxicillin (20 mg/ml) and cefuroxime (200 mg/ml) were performed 30 days later according to standardized procedures 4 . If they were negative, intradermal tests were carried out. Prick test was positive only to cloxacillin in case 1 with a mean diameter of the obtained wheal of 5mm. Prick test were all negative in case 2, but the intradermal test was positive to cloxacillin (2 mg/ml) presenting a 14 mm wheal of mean diameter, double that of the histamine wheal (1 mg/ml) at the 20 min. reading. All the other tests were negative and no positive results were obtained at the 24 h reading. Simple-blind oral challenge tests with increasing doses until an accumulative dosis of amoxicillin (1 g) and cefuroxime (500mg) were performed, being well-tolerated in both patients.

DISCUSSION

Adverse reactions to betalactam antibiotics constitute a major hazard in medical practice.

Although the use of cloxacillin is widely extended, data of immediate allergic reactions after using this drug are very scarce. It could be explained due to it is not frequently involved in allergic reactions 5 but there could exist an inssufficient communication that leads to remain cloxacillin allergic reactions to be underdiagnosed. This fact could explain the lack of reported experience in clinical management of those patients. There is a general tendency to avoid using other betalactam antibiotics due to that there are similarities in chemichal structure between them to justify a cross-reactivity mechanism between cloxacillin and amoxicillin or cephalosporins.

However, if we remember that many of the allergic patients to penicillin or amoxicillin tolerate any cephalosporin, the allergologist might be asked to find out which of the other betalactam antibiotic could be used as secure alternatives in cloxacillin allergic patients. We should not forget that previous observations indicate that, in some instances, subjects allergic to cloxacillin may experience an allergic reaction after taking the drug orally but have good tolerance after being administered the same drug by parenteral route 6 .

In conclusion, we present two different patients allergic to cloxacillin with normal tolerance to other betalactam antibiotics, confirming that cross-reactivity seems to be uncommon among those tested antibiotics. A complete allergologic study, including an oral challenge test, should be considered in these patients.

Correspondence:Dr. Javier Dominguez OrtegaUnit of Allergy. Hospital Universitario de GetafeCtra. de Toledo. Km. 12,500.28905 Getafe. Madrid. Spain.E-mail: jdort@mixmail.com

Referencias Bibliográficas:

Importante

-->1. Novalbos A, Bombin C, Figueredo E, Lluch M, Sastre J. Localized pustulosis induced by betalactams. J Investig Allergol Clin Immunol 2000;10:178-9.
2. Dodek P, Phillips P. Questionable history of immediate type hypersensitivity to penicillin in Staphylococcal endocarditis- treatment based on skin test results versus empirical alternative treatment. A decision analysis. Clin Infect Dis 1999;29: 1251-6.
3. Gamboa P, Jauregui I, Urrutia I, Gonzalez G, Antepara I. Contact sensitization to cloxacillin with oral tolerance to other betalactam antibiotics. Contact Dermatitis 1996;34:75-6.
4. Silviu-Dan F, McPhillips S, Warrington RJ. The frequency of skin test reactions to side-chain penicillin determinants. J Allergy Clin Immunol 1993;91:694-701.
5. Ponvert C, Le Clainche L, de Blic J, le Bourgeois M, Cheinmann P, Paupe J. Allergy to beta-lactam antibiotic in children. Pediatrics 1999; 104:e 45.
6. Torres MJ, Blanca M, Fernández J, Esteban A, Moreno F, Vega JM, García J. Selective allergic reaction to oral cloxacillin. Clin Exp Allergy 1996;26:108-11.

Allergologia et immunipathologia

Antibiotic Effective Against Leading Cause of Blindness Throughout the World

A Single Dose of One Antibiotic for Treating Trichiasis is More Effective than a Six-week Regimen of Another Antibiotic

A clinical trial funded by the National Eye Institute (NEI), part of the National Institutes of Health (NIH), has concluded that a single dose of azithromycin taken by mouth after surgery reduces by one-third the recurrence of a vision-threatening eyelid condition called trichiasis. This is in contrast to the usual six-week regimen of tetracycline ointment applied directly to the eye. This study is published in the March 2006 issue of Archives of Ophthalmology.

“This study illustrates the importance of NIH clinical trials to find treatments for diseases that affect people throughout the world,” said Elias A. Zerhouni, M.D., director of the NIH. “When we consider that an estimated 11 million people worldwide develop trichiasis every year, we see the impact that the findings of this study may have in preventing future vision loss.”

Trichiasis is a condition in which the eyelid turns inward and eyelashes rub against the eye, resulting in corneal scarring and loss of vision. It results from trachoma, an eye infection that is the leading preventable cause of blindness in the world. It is spread through contact with flies and other insects, clothing or household items that harbor the bacterium, or infected people.
Trachoma occurs in poor, overcrowded communities that have little access to clean water, waste treatment facilities, or health care. These communities are located mainly in Africa, the Middle East, Asia, Australia and some areas of Latin America.

The World Health Organization (WHO) previously endorsed a multi-faceted strategy to control trachoma, including surgery for trichiasis and application of tetracycline after surgery.
In this study, called Surgery for Trichiasis, Antibiotics to Prevent Recurrence (STAR), eye infection with the bacterium that causes trachoma was present in 19 percent of the adults with trichiasis in Wolayta Zone, Ethiopia, the location of the clinical trial. More than 77 percent of the patients were women, who have four times the rate of trichiasis than men. Women often contract trachoma repeatedly by taking care of infected children.

“This clinical trial was relatively inexpensive to conduct, and produced results that may well save the vision of millions of people,” said Paul A. Sieving, M.D., Ph.D., director of vision research at NIH. “We look forward to supporting future trials to treat blinding eye diseases worldwide.”

“The simple surgical repair of the eyelid to prevent blindness has been plagued by high rates of recurrence of trichiasis — up to 50 percent in some areas,” said study chairman Sheila K. West, Ph.D., Wilmer Eye Institute, Johns Hopkins University. “In this study, by administering a single dose of azithromycin after eyelid surgery, we were able to reduce recurrence of trichiasis by 33 percent. This finding has major implications for improving the outcome following surgery.”
Continuing, Dr. West explained, “Some of the high rate of recurrence, no doubt, is due to poor surgical technique. Surgeons should be well trained and certified to ensure optimal outcomes. Future trials will need to standardize the procedure when testing surgical therapies.”

For this trial, the researchers from Wilmer Eye Institute partnered with ORBIS International, a nonprofit organization that works to eliminate blindness in developing countries. ORBIS trained Integrated Eye Care Workers (IECWs) to perform the eyelid surgeries, and Wilmer Eye Institute certified them, following WHO guidelines to ensure quality. The surgeries performed by the IECWs were as successful as those performed by ophthalmologists, and recurrence rates overall were low.

The results of this clinical trial, Dr. West believes, are transferable to other settings because most countries with widespread trichiasis now have access to a free azithromycin distribution program.

Thomas Quinn, M.D., an investigator with the National Institute of Allergy and Infectious Diseases, another component of NIH, and Johns Hopkins University, was a collaborator and co-author on the study.

Pfizer, Inc., through the International Trachoma Initiative that it co-sponsors with the Edna McConnell Clark Foundation, provided the azithromycin used in this trial.

For more information about eye health, the causes and treatment of vision problems and much more, visit the National Eye Institute Web site at www.nei.nih.gov.

The National Eye Institute is part of the National Institutes of Health (NIH) and is the Federal government’s lead agency for vision research that leads to sight-saving treatments and plays a key role in reducing visual impairment and blindness. The NIH is an agency of the U.S. Department of Health and Human Services.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov

Article

Antibiotics for Irritable Bowel Syndrome?

Novel Treatment For Irritable Bowel Syndrome Patients

February 15, 2006 12:30 p.m. EST

Ayinde O. Chase - All Headline News Staff Writer

Lebanon (AHN) - Researchers discovered that rifaximin, an antibiotic used to treat diarrhea, is also effective in treating abdominal bloating and flatulence, including in irritable bowel syndrome patients.

Researchers at American University of Beirut in Lebanon treated 124 patients with rifaximin therapy and found that it was effective at relieving the symptoms of bloating and excess gaseousness by way of reducing the amount of hydrogen gas produced in the large intestine.

Researchers published their data and findings in the February issue of The American Journal of Gastroenterology and also note because rifaximin is non-absorbable, there are no side effects, making it viable for chronic use.

All Headline News

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Related Story

Is IBS a Bacterial Infection?

By: William E. Whitehead, Ph.D., Professor of Medicine and Co-Director, University of North Carolina Center for Functional GI and Motility Disorders

A recent article by Dr. Mark Pimentel and colleagues at Cedars-Sinai Medical Center caused a great deal of excitement because it suggested that irritable bowel syndrome is a bacterial infection that can be treated with antibiotics [1]. These claims were widely reported in newspapers [2]. If they are true, then the understanding and management of IBS will be revolutionized. However, a careful reading of the study suggests caution.

The authors made two important observations: first, that 78% of IBS patients had small bowel bacterial overgrowth and second, that eradication of bacterial overgrowth decreased the symptoms of diarrhea and abdominal pain and "cured" IBS in 48%. Let's take these observations one at a time.

The patients who entered this study were not a representative group of IBS patients; they were patients who were referred for breath testing because their doctors suspected they had small bowel bacterial overgrowth. Selecting patients for testing in this way may have led to an overestimation of the proportion of IBS patients who have small bowel bacterial overgrowth. The only way to know what proportion of IBS patients have small bowel bacterial overgrowth is to test a large, representative group of patients.

The criteria for diagnosing small bowel bacterial overgrowth may also have been rather liberal. The investigators appropriately considered a test as positive only if they saw two peaks in breath hydrogen concentration, one representing intestinal bacteria and the second representing bacteria in the colon. However, they are unclear how high the first peak had to be for the test to be considered positive. Their rate of positive tests was much higher than expected; for example, out of 144 tests for suspected small bowel bacterial overgrowth carried out in our laboratory during a one year period, only 28% were positive.

It is also difficult to evaluate the authors' claim that eradication of abdominal pain and diarrhea with antibiotics "cures" IBS because only 30% of the IBS patients treated with antibiotics returned for evaluation. This was a retrospective study, so it was left to the discretion of the primary physician (not the investigators) which antibiotics were used to treat and whether the patient was asked to return for testing. It is important to know whether the other 70% were not sent back because they no longer had symptoms or whether they were not sent back because diagnosis and treatment of small bowel bacterial overgrowth made no difference, so their doctors had moved on to other tests.

Quite apart from these concerns about the study design, there is a question whether these patients should be diagnosed as IBS. The Rome criteria [3] state that a patient should be diagnosed IBS if they have a sufficient number of a list of positive symptoms (which these patients had) and if there is no alternative, disease explanation for these symptoms. Many gastroenterologists are aware that small bowel bacterial overgrowth can produce symptoms similar to IBS, just as inflammatory bowel disease and lactose malabsorption can; they do not label a patient as IBS if there is evidence for one of these alternative diagnoses.

Although it is premature to conclude that the authors have found the cause and the cure for IBS, they have drawn attention to the fact that small bowel bacterial overgrowth is a relatively common condition that can cause symptoms suggestive of IBS. This may have the beneficial effect of causing physicians to consider this diagnosis more frequently, to test for it, and to treat appropriately when it is found.

However, antibiotics should only be prescribed when there is definite evidence of small bowel bacterial overgrowth because antibiotics occasionally cause harmful side-effects, and their indiscriminant use may lead to the development of antibiotic-resistant strains of bacteria.

References:

[1] Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 2000;95:3503-3506.
[2] Beasley D. Study links intestinal bacteria to irritable bowel syndrome. Reuters, Los Angeles, December 13, 2000.
[3] Thompson WG, Longstreth G, Drossman DA, Heaton K, Irvine EJ, Muller-Lissner S. Functional bowel disorders and functional abdominal pain. In: Drossman DA, et al. Rome II: The functional gastrointestinal disorders, 2nd edition. Degnon Associates, McLean, Va, 2000. Pp 351-432.

For more on this topic, read the comments of Dr. Douglas Drossman

About IBS

Mass Antibiotic Treatment Doesn't Thwart Eye Disease

HealthDayBy Robert PreidtTuesday, March 7, 2006

TUESDAY, March 7 (HealthDay News) --

A single mass antibiotic distribution is not an effective way to treat and eliminate trachoma -- an eye infection that can cause blindness -- in Ethiopian communities with high rates of the disease.

That's the conclusion of a study in the March 8 issue of the Journal of the American Medical Association.

Community-wide antibiotic distributions are part of the World Health Organization's strategy to eliminate trachoma as a public health concern by 2020. It has been suggested that a single mass antibiotic treatment in a community might eliminate trachoma. However, current WHO guidelines recommend three mass distributions per year.

To assess this approach, researchers monitored eight Ethiopian villages for up to 24 months after all residents over 1 year old were offered a single oral dose of the antibiotic azithromycin. Fifteen other villages were enrolled 12 months into the program.

The researchers, led by Jaya D. Chidambaram of the University of California, San Francisco, focused on children aged 1 to 5, because they have the highest rates of trachoma and may form the core group for transmission of the infection.

Prior to treatment, the average prevalence of infection in the children was 43.5 percent. By two months after the mass treatment, the rate was 5.1 percent. Two years after the treatment, the infection rate was 11.3 percent.

"Our results suggest that if infection is not eliminated by a single mass antibiotic treatment, then it predictably returns into the community, at least in this hyperendemic (area of high prevalence) area in 1- to 5-year-old children," the study authors wrote." However, infection comes back slowly and does not approach baseline prevalence even by two years."
They concluded that "repeated treatments or other measures will be necessary for elimination of infection, as recommended by WHO. A single treatment will not suffice."

HealthDay

Antibiotic Found to Cause Blood-Sugar Ailments in Seniors

March 2, 2006

Elderly patients taking the widely used antibiotic gatifloxacin were almost 17 times as likely to be hospitalized for very high blood sugar levels and four times as likely to be hospitalized for unusually low levels, a finding that is leading some physicians to call for the drug's withdrawal from the market.

Overall, one of every 100 patients who took the drug was hospitalized, according to a study released online Wednesday by the New England Journal of Medicine. The study was released before its March 30 publication because of its health implications.

Several previous studies have shown an increased risk of glucose abnormalities and several deaths in diabetic patients who received the antibiotic, trade-named Tequin. The drug's label was changed last month to say it should not be given to diabetics. The latest study, which is larger and more definitive, showed that all patients were at risk, even those who were not diabetic. The study's authors said that because other antibiotics were as effective, there was no reason to continue prescribing gatifloxacin.

"Speaking as a clinician, I would never prescribe this drug," said Dr. David N. Juurlink of the Institute for Clinical and Evaluative Sciences in Toronto, who led the study.

Dr. Sidney Wolfe of the Public Citizen Health Research Group in Washington, D.C., said: "This represents a unique danger in the absence of a unique benefit…. This is more than enough reason to think about petitioning the Food and Drug Administration to ban the drug, and we probably will.

"Eric Miller, a spokesman for Bristol-Myers Squibb Co., which makes Tequin, said that the findings "were consistent with the post-marketing experience we have had to date." He said the labeling changes in February took the findings into account.

Miller said the company's annual sales of the drug were about $100 million in the United States and $150 million worldwide — a relatively minor portion of Bristol-Myers' $19.4 billion in total revenue.

Gatifloxacin is a member of the family of broad-spectrum antibiotics known as fluoroquinolones.

It is typically used to treat gonorrhea and lung, sinus and urinary tract infections. Physicians often use it when the nature of an infection is unknown, Juurlink said, because it kills a wide variety of bacteria.But the quinoline family has proved problematic. Four other fluoroquinolones have been withdrawn from the market or had their use severely restricted: temafloxacin, for causing red blood cell damage, kidney failure and hypoglycemia; grepafloxacin and sparfloxacin because of heart problems; and trovafloxacin because of liver damage.

"That is an alarming proportion of drugs in that class that have been taken off the market," said Wolfe of Public Citizen.Gatifloxacin was introduced in 1999. By 2001, 3.3 million prescriptions per year were being written.

Researchers began noticing health problems that year, particularly alterations in glucose metabolism. Changes in blood sugar levels can induce coma and other serious problems, including death. Symptoms usually began five to 10 days after patients took the drug. In most cases, the symptoms could be reversed when drug use was halted.

By 2003, 17 deaths had been linked to the drug and prescriptions were down to about 1.7 million per year.One major contributor to that number is the Department of Veterans Affairs, which added the drug to its formulary and designated it an antibiotic of first choice, in part because Bristol-Myers offered the government a price of $1.35 per pill, compared with the $8 to $10 per pill charged for it and other fluoroquinolones at pharmacies, said Dr. Richard Frothingham of Duke University.

The government also chose it because the risk of glucose abnormalities caused by gatifloxacin did not seem to be any higher than that caused by other antibiotics in the class, Juurlink said.In light of the new findings, he said, "the VA needs to very promptly revisit their policy.

"The Canadian researchers studied health records for 1.4 million Ontario residents over age 65. Among them were about 17,000 gatifloxacin patients.

Juurlink and his colleagues then looked at all patients who had been hospitalized after taking an antibiotic. They found 788 were hospitalized for excessively low blood sugar within 30 days of taking an antibiotic and 470 patients hospitalized for excessively high blood sugar.Within that group, there were 61 gatifloxacin recipients with hypoglycemia and 86 with hyperglycemia.

Compared with other patients in the group, the gatifloxacin recipients had four times the risk of hypoglycemia and 17 times the risk of hyperglycemia.

"This is the most compelling evidence to date showing a connection between gatifloxacin and glucose problems," Frothingham said.

No other fluoroquinolone showed an unusual risk.

Juurlink said the study probably underestimated the risks of the drug. "If they died at home or in a pre-hospital setting, they would not have made it into the study," he said.

LA Times

Antibiotic work afflicted by the bottom line blues

March 1, 2006

BY LAURA BEIL
The Dallas Morning News

DALLAS - Sylvia LaRue had been a nurse long enough to know that the golf-ball size lump shooting pain into her scalp was a staph infection. The test results still stunned her.

"I've been a nurse since 1977, and I've never seen a lab report like that," LaRue said of her 2004 encounter with Staphylococcus aureus. The bacteria were resistant or just marginally vulnerable to 10 of the 11 medicines on the list. The single option left to her was trimethoprim/sulfa - not a creation of high-tech science, but a combination developed decades ago.

In the modern antibiotic era, the old drugs are often the only drugs. Many of the world's pharmaceutical giants are losing interest in the pursuit of new antibiotics and slashing their antimicrobial research divisions. At the same time, the germs continue to strengthen their ability to defy the drugs already on the market.

Already, some patients are left with only one or two useful medications. As resistance climbs and research interest falls, infectious disease experts worry about a day when some infections may reach the point of being virtually unstoppable.

"I don't think it's a crisis right now," said Dr. George McCracken, head of infectious disease at Children's Medical Center Dallas. But it might be, he says, "in the next three to five years."
He and other experts are most concerned about the microbes that breed in hospitals, such as staph, pseudomonas and vancomycin-resistant enterococci. These germs seize on weakened patients connected to tubes that offer bacteria inviting portals to the body's innermost reaches. About 2 million people each year will contract an infection they didn't have upon admission.
"In most American hospitals, we are going to have at any point in time somewhere between one and two patients where we have to scramble to find adequate treatment," said Dr. John Bartlett, head of infectious diseases at Johns Hopkins University School of Medicine.

Once, new antibiotics flowed readily. Between 1935 and 1968, 11 new classes of antibiotics - a "class" targets bacteria in a unique way - came on the market. After that, none appeared for more than 30 years. One was approved in 2000, with two more in 2003 and 2005. But those newest antibiotic classes were the outcome of research that began more than a decade ago. Today, doctors lament the paucity of new drugs in the wings and say much of what are in the pipeline are simply updated versions of old medications.

Since 2000, some of the household names in the drug business - including Wyeth, Aventis, Eli Lilly, Bristol-Myers Squibb, Abbott Laboratories - have cut or eliminated antibiotics research. The reasons are complicated, but the bottom line is still about money. Drug companies are amassing into ever-larger conglomerates, and Wall Street is demanding the highest possible profit margins. From a strictly business standpoint, the most attractive prescription is the one taken by a lot of patients for a long time.

A successful new antibiotic - generally designed to be taken for short periods - might reap a few hundred million dollars a year during its brand-protected life. Compare that with the cholesterol-lowering Lipitor, which a patient might take for a lifetime. It brought in more than $12 billion to Pfizer in 2005. Among the top 20 prescription sellers last year, none was an antibiotic.

"These are critically important drugs. They save lives, and they save them fast," said Steven Projan, vice president of biological technologies for the drug giant Wyeth, which abandoned antibiotics discovery in 2002. But the reality is, "the therapy is going to be for three days to two weeks. It's not like you're giving somebody Lipitor for the rest of their lives."

Other issues, however, both scientific and regulatory, also discourage antibiotics research, Projan said. Antibiotic development can be harder than other drug endeavors, he believes, "and it's harder for reasons we are just starting to understand."

Bacteria have occupied the planet longer than humans, evolving sophisticated mechanisms to outsmart chemical assaults. Most of the current antibiotics, often found by accident, are based on substances extracted from other living things that have spent eons refining the tactics of chemical warfare. Today, the vein of natural compounds largely has been mined, and more modern approaches - techniques that rely on disabling a microbe's inner genetic machinery - have been disappointing.

When drug maker Eli Lilly & Co. mulled its future direction in 2002, the feeling was that "this is one area of drug discovery where I think the low-hanging fruit had been picked," said vice president Gail Cassell.

Each company has its own reasons for leaving antibiotic research, said Cassell, who is a microbiologist. "We consciously made the choice to focus our efforts in the area of oncology, diabetes and neuroscience. We viewed those as equally unmet needs."

Companies who continue to pursue antibiotics say they aren't expecting breathtaking payoffs. "This is not something that is a major blockbuster type of product," said Dr. Lynn Marks of GlaxoSmithKline, which submitted a new topical antibiotic for FDA approval in February. "I think our stockholders understand there's more to being a great corporation that just turning pure profit."

But where many big pharma companies see anemic profits for enormous effort, small entrepreneurs see opportunity. "Where it's happening," McCracken said of antibiotics research, "is with the small companies."

Biotech companies don't depend on a Lipitor-scale return.

"If we made $100 million, that would be real money to us," said Simon Lynch, director of research for Dallas-based Cumbre Inc. And smaller companies tout themselves as being leaner and more passionate than their famous counterparts, knowing that their entire survival depends on having a product to show for their time.

Companies like Cumbre have maybe two dozen or so research scientists, while the larger firms might employ hundreds. Yet finding a drug isn't necessarily a matter of having the most Petri dishes.

For example, Cumbre is tightly focused on defeating biofilm infections - the slimy, often impenetrable communities of bacteria that can coat the insides of catheters and the surface of bones.

But can small pharma succeed where big pharma can't? Wyeth's Projan remains skeptical. "We have a huge amount of experience doing this, and they tend to make all the mistakes we do," he said. He says he believes in the need; the last approved new drug class was a Wyeth invention. A turnaround in antibiotic discovery, he said, will depend on better innovation, not just better economics.

"What we need are new chemistries. We've been stuck in the solar system, and we need to get out into the galaxy."

Lynch's company, for example, is looking at how a bacterium shields itself from a chemical that would otherwise kill it. Many potential drugs don't work because bacteria have molecular pumps that enable them to bail out foreign chemicals as quickly as they come in. Disabling those pumps would allow antibiotics to become trapped in cells.

Other companies are exploring how to jam the communications that allow bacteria to sense one another's presence and, in essence, transform from a disorganized militia into a precision-trained force. Working together, bacteria can become meaner and more resistant to drugs than they could ever be in lesser groups.

"The optimistic view is that some of these biotechs are going to hit paydirt," said David Shlaes of Connecticut-based Anti-Infectives Consulting. "They will challenge big pharma in the marketplace, and big pharma is going to wake up."

Doctors have also taken proposed solutions to Congress, including measures that would provide financial incentives for antibiotic research and streamline clinical trials. However, some experts point out that more favorable regulation, by itself, won't bring new chemicals into the research pipeline.

Doctors campaigning for more antibiotics research are not against making money, said Dr. Richard Wenzel of Virginia Commonwealth University. The pharmaceutical industry is "driven by the free enterprise system in a straightforward, American way.

"We need drug companies to be able to make a profit," he continued. "The real question is how much when the public's health is at risk."

It's a public health issue that Beverly Perry hadn't considered until November, when her mother, Jean Baccus, suffered a stroke. Five days after Baccus entered the hospital, bacteria invaded her IV line and set up an outpost in her spine.

More than three months later, Baccus' stroke rehabilitation can't begin because the drug-resistant staph infection hangs on.

"You think, `OK, let's give her antibiotics and get it over with,'" Perry said. The stubbornness of the infection astonished her. "We tell her, `It's just going to be a couple more weeks.'"
And a couple of weeks turn into a couple more weeks. Baccus now must be taken to the hospital each day for antibiotic infusions that are sluggish in working. "She's in so much pain," Perry said. "I think everybody needs to know how serious this is."

Article

Antibiotic, supplement may aid Parkinson’s

Government study suggests minocycline, creatine slow worsening of disease

Associated Press
Updated: 2:42 p.m. ET Feb. 23, 2006

WASHINGTON - An antibiotic and a muscle-related compound are leading candidates for a major government study of whether certain compounds could slow the worsening of Parkinson’s disease.

A pilot study, unveiled Thursday, suggests the two — the antibiotic minocycline and creatine, a substance produced in muscle tissue — may have some benefit.
“We are not concluding that these agents are useful, just that they are not useless,” cautioned Dr. Karl Kieburtz of the University of Rochester, who led the study.

It’s far too early for patients to seek the pills, stressed Dr. Diane Murphy, who oversees Parkinson’s research at the National Institutes of Health, which funded the work.

But in the study of 200 patients in the earliest stages of the disease—they didn’t yet require medication for its symptoms—those who took either of the two pills didn’t seem to decline quite as rapidly as those given a dummy pill, scientists said Thursday at Parkinson’s meeting in Washington.

The compounds are thought to lessen a type of cellular stress or fight inflammation that may damage cells.

About 1.5 million Americans have Parkinson’s disease, which gradually destroys brain cells that produce dopamine, a chemical crucial for the cellular communication that controls muscle movement. As dopamine levels drop, symptoms increase: tremors in the arms, legs and face; periodically stiff or frozen limbs; slow movement; impaired balance and coordination.
Standard treatments are to replace lost dopamine with the drug levodopa, and a brain implant to control tremors. Both work for a while, but can’t stop the disease’s inevitable march.

Who gets Parkinson's Disease?

So NIH’s National Institute of Neurological Disorders and Stroke is on a hunt for drugs that might protect patients’ remaining dopamine-producing cells, a so-called neuroprotector. The holy grail would be a simple, easy-to-take pill that would lower the risk of worsening Parkinson’s much like an aspirin a day can lower people’s risk of heart attacks.

“We’re looking for the aspirin of Parkinson’s disease,” is how Murphy puts it. “We don’t have a drug like that right now, and we don’t know of such a drug,” she cautions.

That’s where the pilot study comes in. NIH asked Parkinson’s specialists for a list of potential neuroprotective compounds — substances that could enter the brain and seemed promising in animal studies. From an initial list of 60, they settled on four to pilot-test. The minocycline and creatine results are first in, published in the journal Neurology online this week and announced Thursday at the World Parkinson Congress. Now being analyzed is a similar study on the dietary supplement coenzyme Q-10 or CoQ10 and an experimental drug thought to help repair damaged nerves.

Next up, NIH plans to test the top candidates in a large study to prove whether any of them truly work.

Minocycline is a prescription-only antibiotic, but creatine is available in dietary supplements. Murphy cautioned that over-the-counter preparations of creatine or CoQ10 may not be the same strengths as are under study.

Article

Vancomycin: can we teach the mainstay of therapy for gram-positives new tricks?

Infectious Disease News

February 2006

Future studies will examine the role of vancomycin therapeutic drug monitoring in treating gram-positive infections.

by Megan Goodwin, PharmD, and Elizabeth Dodds Ashley, PharmD, BCPSSpecial to Infectious Disease News

Vancomycin, the only available glycopeptide antibiotic in the United States, continues to be a mainstay of therapy for gram-positive infections, especially methicillin-resistant Staphylococcus aureus (MRSA). With the incidence of MRSA exceeding 50% at many institutions, vancomycin is frequently used as part of empiric regimens as well as for treatment of documented infections.
Optimizing therapy with vancomycin is a challenge for clinicians due to several factors, including interpatient variability in pharmacokinetics. Therefore, serum concentration monitoring is often performed to ensure efficacy while preventing toxicity. One large problem, however, remains for vancomycin: the lack of standardized targets for serum concentration monitoring.

It has been historically believed that both the nephrotoxicities and ototoxicities associated with vancomycin occur as a result of elevated serum concentrations. Evidence, however, confirming causality of this theory is lacking. Most vancomycin-induced toxicity initially described was a result of older, impure formulations. The new, cleaner preparations are associated with a much lower incidence of these reactions. It is known that concomitant medications as well as underlying disease states have been and remain important risk factors for these adverse events. Still, it is generally believed that serum concentrations between 80 and 100 µg/mL may be linked to vancomycin toxicity.

Determining the appropriate target for efficacy is an even more challenging decision. Owing to the time-dependent killing properties of vancomycin, serum trough concentrations are the kinetic parameter most closely related with efficacy. Historically, a trough concentration in the range of 5 to 10 µg/mL was desired. This would easily achieve the goal concentration at two to four times the minimum inhibitory concentration (MIC) for commonly encountered organisms.
More recently, however, this target is being re-evaluated due to increasing vancomycin MICs and the growing number of vancomycin therapeutic fail ures. Some investigators have shown that MICs for Staphylococcus sp. to vancomycin have not been increasing in recent years.

Rather, perhaps “underdosing” of vancomycin is not new and has been associated with failures for decades. Independent of the reason, many clinicians are now targeting higher troughs for vancomycin (from 15 to 20 µg/mL), especially when treating more deep-seated infections (ie, meningitis, endocarditis, osteomyelitis), in which vancomycin penetration may also be an issue.

In 2005, the publication of two new sets of treatment guidelines gave clinicians published target vancomycin monitoring parameters for the first time. These recommendations are based on expert opinion, however, and remain somewhat controversial.

Pneumonia guidelines

The recent pneumonia guidelines, a joint publication from the American Thoracic Society and the Infectious Diseases Society of America (IDSA), advocate targeting higher vancomycin trough concentrations. Vancomycin is a large molecule, and we have known for sometime that penetration into the lung and other infection sites may be difficult. Therefore, increasing the target trough serum concentrations may result in higher pulmonary drug concentrations.

The recommended target vancomycin trough in these guidelines is 15 to 20 µg/mL. However, there are no specific data to say that troughs more than 15 µg/mL are associated with improved outcomes over trough levels more than 5 or 10 µg/mL. Two recent studies that compared linezolid (Zyvox, Pfizer) with vancomycin for nosocomial pneumonia were not able to find a difference between the two medications regarding treatment outcomes. However, a post hoc analysis of the combined results of the two trials showed that in patients with confirmed MRSA pneumonia, linezolid was associated with better survival and clinical cure rates. When these two studies are analyzed, one has to consider vancomycin dosing and monitoring. It appears that most patients received 1 g of vancomycin every 12 hours (a standard, nonpatient-specific dose), and plasma concentrations were not documented nor specifically targeted. For this reason, many believe that the only reason linezolid appears superior in this retrospective analysis is that vancomycin was not appropriately dosed in each patient. Hence, the recommendation in the new guidelines is higher than more traditional regimens. We hope future studies will be designed to compare clinical outcomes in patients treated with “properly dosed” vancomycin and other antimicrobials with anti-MRSA activity.

Endocarditis guidelines

Similarly, the American Heart Association in conjunction with the IDSA revised treatment recommendations for endocarditis in June 2005. The recently published endocarditis guidelines also recommend specific target concentrations for vancomycin.

Because many clinicians consider the vegetations involved in endocarditis to be relatively difficult to penetrate, the traditional target troughs were 15 to 20 µg/mL for this infection. The recent guidelines, however, recommend a lower trough concentration of 10 to 15 µg/mL. As with the pneumonia guidelines, these targets reflect the opinion of the expert panel in the absence of data to document the ideal target. As endocarditis typically presents with positive blood cultures and the location of the infection is actually inside the vascular system, the target trough of 10 to 15 µg/mL is likely reasonable. Endocarditis is also treated for a relatively long time depending on the cause and type of infection. Therefore, IV antibiotics, including vancomycin, may be continued for two to six weeks. In this situation, the targeting of vancomycin troughs of 10 to 15 µg/mL may help reduce the incidence of vancomycin toxicity.

The inclusion of peak concentration monitoring in these guidelines is intriguing. The expert panel recommended a target peak concentration of 30 to 45 µg/mL. Most clinicians rely solely on trough concentration monitoring given the predictable intrapatient kinetics of this agent and the lack of strong association for efficacy or toxicity with peak concentrations. There are specific instances in which measurement of vancomycin peak concentrations has historically been considered clinically important. These include infections located in sites that are difficult to penetrate and include central nervous system (CNS) infections, bone and joint infections and pneumonia. However, the clinical relevance or correlation of improved outcomes and specific peak concentrations has not been proven.

Therapy for resistant gram-positive infections remains challenging. Treatment strategies for these infections are evolving given the availability of new drugs and an increasing understanding of the appropriate administration for older agents. One such example is vancomycin, in which treatment regimens remain suboptimal and ill defined despite more than 50 years of use. These two recent publications are the first to document targets for vancomycin therapeutic drug monitoring. Hopefully, this will aid clinicians in maximizing efficacy of vancomycin therapy. Future studies will document the appropriateness of these recommendations and the role of vancomycin therapeutic drug monitoring in treating these infections.

For more information:

American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.

Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anethesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005;111:3167-3184.

Elizabeth Dodds Ashley, PharmD, is a clinical pharmacist in Infectious Disease, and Megan Goodwin, PharmD, is a pharmacy practice resident, at Duke University in Durham, N.C.

Anxious About Antibiotics? Read This

FEBRUARY 20, 2006 03:01

by Jin-Han Lee (likeday@donga.com)
Korea News

In order to prevent the misuse of antibiotics, the government recently revealed a list of hospitals and clinics that prescribe high amounts of antibiotics.

The most commonly prescribed antibiotics, "-mycins," have played a great role in prolonging human life expectancies by eliminating germs. However, overuse of antibiotics will cause germs to gain resistance, and a vicious cycle where stronger antibiotics are used to kill stronger germs is being repeated. But we cannot afford to renounce antibiotics, either.

Professor Baek Gyeong-ran of Seoul Samsung Hospital’s Infectious Diseases Department says, “The abuse and overuse of antibiotics gives people the misconception that avoiding or taking small amounts of antibiotics is good. But reducing the amount or period of antibiotic treatments causes germs to become more tolerant.”

Let’s look at some common illnesses that require antibiotics and find out how to correctly take them.

Cases Where Antibiotics are Unnecessary—

About 90 percent of enteritis cases, otherwise known as viral or bacterial intestinal infections, in children are caused by viruses like rotaviruses and adenoviruses. These viral intestinal infections cause problems in the upper digestive organs, such as the small intestine and the stomach, and often lead to vomiting, diarrhea, and severe stomachaches.

Kang Jin-han, a pediatrician at the Catholic University of Korea’s Our Lady of Mercy Hospital says, “Rather than using antibiotics, symptoms of viral intestinal infections should be alleviated by antipyretics and pain killers.”

On the other hand, bacterial infections are caused by bacteria in the intestines, leading to liquid or hema feces, and this is when antibiotics are prescribed.

In addition, epidemic keratoconjunctivitis, or “pink eye”-type ocular infections that cause neck pain, bloody eyes, and fever do not call for antibiotics in principle. That is because the condition is naturally cured in about one to two weeks. Ocular medicine, pain relievers, and antichloristic medicines are used to reduce inflammation and pain, instead.

Antibiotics are Absolutely Necessary in the Following Cases—

Urinary infections, such as bladder and urethra infections are commonly caused by germs rather than viruses. Hence, antibiotics are more effective in such cases than other diseases.
Even common colds, if they involve secondary bacterial infections, call for the prescription of antibiotics. The most common illnesses that accompany colds are laryngitis, bronchitis, pneumonia, tympanitis, paranasal sinusitis, and tonsillitis.

In particular, bacterial paranasal sinusitis causes high fever and yellowish nasal mucus. Symptoms of bacterial laryngitis include fever and sore throat, but in the initial stages, it is often mistaken for a common cold. However, when there is no runny nose or coughing, and only high fever and a sore throat, chances are that there will be a white mucus crust inside the throat.

Common cold patients that are highly susceptible to other bacterial infections, such as pneumonia and sinusitis, are also prescribed antibiotics as precautionary measures. That is the reason why 30 to 40 percent of cold patients are prescribed antibiotics.

Varicella, or chicken pox, is also a viral disease that doesn’t need antibiotics. The blisters on the skin caused by it can become infected, however. Antibiotics are used to prevent that from happening.

On the other hand, eye sty cases are mostly bacterial infections, calling for ocular antibiotic ointments and ingested antibiotics.

The Correct Way to Take Antibiotics—

Time is very important when taking antibiotics. One should take antibiotics at regularly timed intervals. For example, if a patient is taking antibiotics three times a day, it is better to take them at eight-hour intervals rather than after meals. If the timing of antibiotic ingestion is irregular, the antibiotic-levels in the blood will fall below an effective level, and the dying germs will once again attack the body. That is why it is critical to take them regularly, even though it can be bothersome.

If the patient thinks that his or her condition has improved and stops taking antibiotics, then the illness is likely to recur. If the germs grow tolerant to the antibiotic, then treatments will have to start using another antibiotic, which will result in more antibiotics being taken.

If prescribed drugs don’t seem to be curing a problem, going to other doctors and getting more antibiotic prescriptions is not the answer. It is very likely to increase the germ-tolerance of the antibiotics being taken. The strengths and types of antibiotics are all different, and are used at different stages of illnesses. When these stages are ignored, germs grow more resistant. If one changes doctors, one should tell his or her new doctor about the antibiotics that were previously prescribed.

A side effect of taking excessive doses of antibiotics is damage to the liver and kidneys. If yellow eyes or a reduction in the amount of urine develop while taking antibiotics, consider the possibility of antibiotic side effects.

Diarrhea, fatigue, nausea, vomiting, and rashes are other side effects of antibiotics. Most of them are temporary and will stop after an antibiotic treatment ends.

Article

How Bacteria Persist Despite Antibiotics

Persistence pays off – for bacteria as well as people. Researchers at the Hebrew University of Jerusalem and Rockefeller University in New York have demonstrated the constant presence of antibiotic-tolerant “persistent cells” within bacteria colonies and have shown, through mathematical modeling, how these cells develop into “normal” cells following their survival of even heavy dosages of antibiotics.

The findings have consequences for development of new tactics for overcoming the common problem of resistance by bacteria to medicinal treatment.

It has been known for some time that when an antibiotic is administered to counteract a specific bacterium, not all of the bacterial cells may die. Persistent cells can remain that will reinfect the patient later – the condition we commonly refer to as relapse. What was not known was the exact nature of these persistent cells nor how they function.

In their research with E. coli bacteria, the Hebrew University and Rockefeller University researchers discovered that persistent cells are a kind of reserve population that is constantly being produced within bacteria, regardless of whether the bacteria are being attacked by an antibiotic or not. These cells are slow-growing and – apparently because of their “retarded” or “non-mature” state – are not susceptible to antibiotics.

Translating their observations into a mathematical model, the researchers have shown how these persistent cells slowly but surely continue growing until they reach a “normal” growth stage. At that point, the former persistent cells are now themselves susceptible to antibiotic attack.

The work of the researchers – Prof. Nathalie Questembert-Balaban, head of the biophysics laboratories at the HU Racah Institute of Physics; Prof. Stanislas Leibler of Rockefeller University; and his students Jack Merrin, Remy Chait and Lukasz Kowalik – appeared in a recent issue of Science magazine.

Prof. Balaban observes that if the timing could be worked out so that the persistent cells could be “hit” with antibiotics at the point that they reach a normal growth stage, then perhaps the problem of relapse could be overcome. Alternatively, perhaps further study of the nature of the persistent cells could lead to drugs that would take direct action against them in their initial state.

The discoveries by the Hebrew and Rockefeller universities scientists might also point in the direction of overcoming the problem of reoccurrence of cancer in patients who have undergone earlier, successful remission.

Slow-growing bacteria cells that are resistant to antibiotic drugs are shown in the magnified illustration at left among the other “normal” bacterial cells, and again at right showing how they have survived after the other bacterial cells have been destroyed by antibiotics. (Illustration courtesy of the Hebrew University of Jerusalem)

Hebrew University of Jerusalem

Taking Generic Form of Drug Boosts Regimen Adherence

HealthDay
By Robert Preidt
Tuesday, February 14, 2006

TUESDAY, Feb. 14 (HealthDay News) -- Patients who take generic prescription drugs are more likely to adhere to their doctor's prescribed therapy plan than patients who take brand-name drugs, a new study finds.

The findings are another reason why "generic drugs should be prescribed for patients beginning chronic therapy, as long as there are no specific clinical reasons why a branded drug may be more appropriate," researcher Dr. William Shrank, of Brigham and Women's Hospital and Harvard Medical School in Boston, said in a prepared statement.

The findings appear in the Feb. 13 issue of the journal Archives of Internal Medicine.
Shrank's group analyzed how well 6,755 patients enrolled in a three-tier pharmacy benefit structure stuck to their drug regimens. Under their benefit plan, the patients had to pay the highest co-payment for non-preferred brand-name drugs (third tier), smaller co-payments for preferred brand-name drugs (second tier), and smallest or no co-payment for generic drugs. The group received a total of 7,532 new prescriptions during the study period.

There were six classes of drugs included in the study: cholesterol-lowering statins; oral contraceptives; orally inhaled corticosteroids (asthma); and three antihypertensives (calcium-channel blockers, angiotensin receptor blockers and angiotensin converting enzyme inhibitors).

Patients who took generic drugs showed a 12.6 percent increase in therapy adherence, compared to patients who took brand-name third-tier drugs, the study found. Patients who took second-tier drugs had an 8 percent increase in adherence compared to those who used third-tier drugs.

Other findings:

Patients who took a generic drug had a 62 percent better chance of achieving adequate adherence and those who took a brand-name second-tier drug had a 30 percent better chance than those who took third-tier drugs.

Patients who were initially prescribed third-tier brand-name drugs were 2.1 times more likely to switch to a drug in another tier than patients initially prescribed generic drugs.

Patients who switched from their initial prescription were 2.8 times more likely to switch to a less-expensive, lower-tier brand-name or generic than to a higher-tier drug.

Patients who initially received generic drugs switched at less than half the rate of those who received third-tier drugs.

"Physicians commonly prescribe chronic medications for important medical problems. Both physicians and patients should be aware of how the medication choice directly influences the patient's ability to follow the prescribed treatment," Shrank said.

Copyright © 2006 ScoutNews LLC

Minocycline

mih noe SYE kleen)

Dynacin, Minocin, Vectrin

What is the most important information I should know about minocycline?

Take all of the minocycline that has been prescribed for you even if you begin to feel better. Your symptoms may start to improve before the infection is completely treated.

Children younger than 8 years of age should not take minocycline. It can cause permanent tooth discoloration, and it can affect growth.

Avoid taking multivitamins, iron supplements, antacids, and laxatives within 2 hours of taking minocycline. These products may decrease the effectiveness of minocycline.

Minocycline may decrease the effectiveness of birth control pills. Use a second method of birth control to prevent pregnancy while taking minocycline.

Avoid prolonged exposure to sunlight. Minocycline may increase the sensitivity of your skin to sunlight. Use a sunscreen and wear protective clothing when exposure to the sun is unavoidable.

What is minocycline?

Minocycline is a tetracycline antibiotic. It fights bacteria in your body.

Minocycline is used to treat many different bacterial infections, such as urinary tract infections, acne, gonorrhea, and chlamydia, among others.

Minocycline may also be used for purposes other than those listed in this medication guide.
Who should not take minocycline?

Before taking minocycline, tell your doctor if you have kidney or liver disease. You may not be able to take minocycline, or you may require a dosage adjustment or special monitoring during therapy.

Minocycline is in the FDA pregnancy category D. This means that it is known to harm an unborn baby. Minocycline may affect bone and tooth development in the developing baby. Do not take this medication without first talking to your doctor if you are pregnant.

Minocycline passes into breast milk and may affect bone and tooth development in a nursing infant. Do not take this medication without first talking to your doctor if you are breast-feeding a baby.

Children younger than 8 years of age should not take minocycline. It can cause permanent tooth discoloration, and it can affect growth.

How should I take minocycline?

Take minocycline exactly as directed by your doctor. If you do not understand these instructions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water (8 ounces).

Minocycline may be taken on an empty stomach or with food or milk.

Do not take iron supplements, multivitamins, calcium supplements, antacids, or laxatives within 2 hours of taking minocycline. These products may reduce the effectiveness of minocycline.

Take all of the minocycline that has been prescribed for you even if you begin to feel better. Your symptoms may start to improve before the infection is completely treated.

Throw away any unused minocycline when it expires or when it is no longer needed. Do not take any minocycline after the expiration date printed on the bottle. Expired minocycline can cause a dangerous syndrome resulting in damage to the kidneys.

Store this medication at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and take only your next regularly scheduled dose. Do not take a double dose of this medication unless otherwise directed by your doctor.
What happens if I overdose?

Seek emergency medical attention.

Symptoms of a minocycline overdose include nausea, vomiting, and diarrhea.

What should I avoid while taking minocycline?

Avoid prolonged exposure to sunlight. Minocycline increases the sensitivity of your skin to sunlight, and severe burning may result. Wear protective clothing and sunscreen if exposure to the sun is unavoidable.

Do not take iron supplements, multivitamins, calcium supplements, antacids, or laxatives within 2 hours of taking minocycline. These products may reduce the effectiveness of minocycline.

Throw away any unused minocycline when it expires or when it is no longer needed. Do not take any minocycline after the expiration date printed on the bottle. Expired minocycline can cause a dangerous syndrome resulting in damage to the kidneys.

What are the possible side effects of minocycline?

If you experience any of the following serious side effects, stop taking minocycline and seek emergency medical attention:

·an allergic reaction (swelling of your lips, face, or tongue, difficulty breathing);
·a severe headache;
·vision changes;
·confusion;
·liver damage (yellowing of the skin or eyes, nausea, abdominal pain or discomfort, unusual bleeding or bruising, severe fatigue);
·blood problems (fever, fatigue, easy bruising or bleeding); or
·genital sores or itching.

If you experience any of the following less serious side effects, continue to take minocycline and talk to your doctor:

·nausea, vomiting, diarrhea, or decreased appetite;
·dizziness or lightheadedness;
·sensitivity to the sun;
·dark "furry" tongue, black tongue, or swollen tongue; or
·vaginal yeast infection.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect minocycline?

Do not take the following drugs within 2 hours of taking minocycline because they may decrease its effectiveness:

·cholestyramine (Questran) or colestipol (Colestid);
·antacids that contain aluminum or magnesium such as Tums or Rolaids;
·bismuth subsalicylate in products such as Pepto-Bismol; or
·minerals such as iron, zinc, calcium, and magnesium, which are found in dairy products (milk, cheese, etc.), and over-the-counter vitamin and mineral supplements.

Before taking minocycline, tell your doctor if you are taking any of the following medicines:
·an anticoagulant such as warfarin (Coumadin); or
·another antibiotic.

You may not be able to take minocycline, or you may require a dosage adjustment or special monitoring during treatment if you are taking any of the medicines listed above.

Minocycline may decrease the effectiveness of birth control pills. Use a second method of birth control to prevent pregnancy while taking minocycline.

Drugs other than those listed here may also interact with minocycline. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

Where can I get more information?

Your pharmacist has additional information about minocycline written for health professionals that you may read.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2003 Cerner Multum, Inc. Version: 6.02. Revision Date: 2/14/03.

........

Medline Plus: Minocycline Oral

Medline Plus: Minocycline Dental

Minocycline - Patient Education

Marinomycins a-d, antitumor-antibiotics of a new structure class

Marinomycins a-d, antitumor-antibiotics of a new structure class from a marine actinomycete of the recently discovered genus "marinispora".

Research Abstract

Kwon HC, Kauffman CA, Jensen PR, Fenical W.

Contribution from the Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92093-0204.

Four antitumor-antibiotics of a new structure class, the marinomycins A-D (1-4), were isolated from the saline culture of a new group of marine actinomycetes, for which we have proposed the name "Marinispora". The structures of the marinomycins, which are unusual macrodiolides composed of dimeric 2-hydroxy-6-alkenyl-benzoic acid lactones with conjugated tetraene-pentahydroxy polyketide chains, were assigned by combined spectral and chemical methods. In room light, marinomycin A slowly isomerizes to its geometrical isomers marinomycins B and C. Marinomycins A-D show significant antimicrobial activities against drug resistant bacterial pathogens and demonstrate impressive and selective cancer cell cytotoxicities against six of the eight melanoma cell lines in the National Cancer Institute's 60 cell line panel. The discovery of these new compounds from a new, chemically rich genus further documents that marine actinomycetes are a significant resource for drug discovery.

PMID: 16448135

[PubMed - in process]

Treatment of plague with gentamicin or doxycycline in a randomized clinical trial in Tanzania.

Mwengee W, Butler T, Mgema S, Mhina G, Almasi Y, Bradley C, Formanik JB, Rochester CG.

Regional Medical Office, Tanga, Tanzania.

trigsby@jhmi.edu.

Background.

Over the past 50 years, antibiotics of choice for treatment of plague, including streptomycin, chloramphenicol, and tetracycline, have mostly become outdated or unavailable. To test gentamicin in the treatment of naturally occurring plague and the implications of its use in the treatment of bioterrorist plague, a randomized, comparative, open-label, clinical trial comparing monotherapy with gentamicin or doxycycline was conducted in Tanzania.

Methods.

Sixty-five adults and children with symptoms of bubonic, septicemic, or pneumonic plague of duration were enrolled in the study. Bubo aspirates and blood were cultured for Yersinia pestis. Acute-phase and convalescent-phase serum samples were tested for antibody against fraction 1 antigen of Y. pestis. Thirty-five patients were randomized to receive gentamicin (2.5 mg/kg intramuscularly every 12 h for 7 days), and 30 patients were randomized to receive doxycycline (100 mg [adults] and 2.2 mg/kg [children] orally every 12 h for 7 days). Serum creatinine concentrations were measured before and after treatment, and peak and trough concentrations of antibiotics were measured.

Results.

Three patients, 2 of whom were treated with gentamicin and 1 of whom was treated with doxycycline, died on the first or second day of treatment, and these deaths were attributed to advanced disease and complications including pneumonia, septicemia, hemorrhage, and renal failure at the start of therapy. All other patients experienced cure or an improved condition after receiving therapy, resulting in favorable response rates of 94% for gentamicin (95% CI, 81.1%-99.0%) and 97% for doxycycline (95% CI, 83.4%-99.8%). Y. pestis isolates obtained from 30 patients belonged to biotype antigua and were susceptible to gentamicin and doxycycline, which had MICs of 0.13 mg/L and 0.25-0.5 mg/L, respectively. Serum concentrations of antibiotics were within therapeutic ranges, and adverse events were infrequent. Patients treated with gentamicin demonstrated a modest increase in the mean serum creatinine concentration after treatment (P<.05, by paired t test).Conclusions. Both gentamicin and doxycycline were effective therapies for adult and pediatric plague, with high rates of favorable responses and low rates of adverse events.

PMID: 16447105

[PubMed - in process]