Sat, 11 Mar 2000

Antibiotics recommended when indicated for treatment of Gulf War Illness/Chronic Fatique Syndrome, Fibromyalgia Syndrome, Rheumatoid Arthritis and other Autoimmune illnesses

by Prof. Garth L. Nicolson


Doxycycline ( Vibramycin, Doxychel, Doxy-D, Doryx)


Doxycycline is a broad spectrum tetracycline with good lipid solubility and ability to penetrate the blood-brain-barrier. This antibiotic acts by inhibiting microorganism protein synthesis; it is readily absorbed by the (normal) gut, and peak blood concentrations are maintained between 2-18 hrs (half-life, 18-22 hrs) after an oral dose of drug. Food, calcium, magnesium, antacids and some drugs reduce absorption, and alcohol, phenytoin Dilantin or barbiturates reduce blood half-life or suppress the immune system. Minocycline Minocin can be substituted, and for some illnesses (RA) it is preferred because it penetrates tissues better (same dose/day).


For GWI/CFS/FMS/RA use, the recommended oral dose is 200-300 mg/day (2-3X 100 mg capsules, 2 in the morning) for 6 months. After 6 months, 6 wk cycles are suggested. Initially, doxycycline can exacerbate chronic signs and symptoms (Herxheimer reactions or adverse responses, such as transient fever, skin, gut discomfort, etc.) but these are usually reduced within a few wks (see first section). Patients usually start feeling better with alleviation of major signs and symptoms within 12 wks, but in some patients’ major symptoms are not alleviated until after 12 wks. Severe reactions or prior damage to the gastrointestinal track may require i.v. administration of 100-150 mg/day (rapid i.v. administration must be avoided) for 2-3 wks, then the remainder of the course should be oral (to avoid thrombophlebitis and other complications that can occur with prolonged i.v. therapy). Some patients react to the starch filler in the capsules and must use Doryx, a granular form of pure doxycycline.
Virtually all patients relapse (show the same major signs and symptoms) if they stop therapy before 6 months. In a pilot study, ~85% relapsed after 12 weeks of therapy, so the first 6 months without a break is recommended.
Doxycycline has been used successfully in addition to other antibiotics in situations where either antibiotic alone had minimal effects (ie., doxycycline plus ciprofloxacin or doxycycline plus azithromycin).


Doxycycline and minocycline are primarily bacteriostatic and effective against the following organisms: gram-negative bacteria (N. gonorrhoeae, Haemophilus influenzae, Shigella species, Yersinia pestis, Brucella species, Vibrio cholera); gram-positive bacteria (Streptococcus pneumoniae, Streptococcus pyogenes); mycoplasmas (Mycoplasma pneumoniae, Mycoplasma fermentans inc. incognitis strain, Mycoplasma penetrans);
others (Bacillus anthracis anthrax, Clostridium species, Chlamydia species, Actinomyces species, Entamoeba species, Treponema pallidum syphilis, Plasmodium falciparum malaria and Borrelia Lyme species).


Precautions: Avoid direct sunlight and drink fluids liberally, especially with oral capsules. Doxycycline or minocycline therapy may result in overgrowth of fungi or yeast and nonsensitive microorganisms (see Considerations, first page). Patients on anticoagulants may require lower anticoagulant doses. Use during pregnancy or in children under 8 years is not recommended, in the latter case due to tooth discoloration, but lower doses of doxycycline have proven to be very effective in children with GWI/CFS (weight 100 lbs or less, 1-2 mg/lb divided into two doses; weight over 100 lbs use adult dose). Patients with impaired kidney function should not take doxycycline, and the following drugs should not be taken with doxycycline: methoxyflurane Penthrane, carbamazepine Tegretol, digoxin or diuretics. Other drugs can effect uptake or immune systems (see above). For complicating bacterial infections, 2 wks Augmentin (3X 500 mg/day) can be taken in between courses of antibiotics. For fungal and yeast complications, please see the instructions above.


Adverse Reactions: In a few patients doxycycline causes gastrointestinal irritation, anorexia, vomiting, nausea, diarrhea, rashes, mouth dryness, hoarseness and in rare cases hypersensitivity reactions, hemolytic anemia, skin hyper-sensitivity and reduced white blood cell counts. In general, doxycycline is considered a very safe drug, in that there are few adverse reactions reported in the literature.


Ciprofloxacin ( Cipro, Cifox, Cifran, Ciloxan, Ciplox)


Ciprofloxacin is a broad spectrum synthetic fluoroquinolone antibiotic with good absorption characteristics. This drug acts on bacterial DNA gyrase to inhibit bacterial DNA synthesis. Ciprofloxacin is secreted rapidly in the urine and has a half-life in the blood of ~4 hrs. Food delays the absorption (by ~2 hrs) but doesn’t effect total absorption; antacids containing magnesium, aluminum or other salts as well as various drugs reduce absorption and should not be taken at the same time of day.


For GWI/CFS/FMS use, the recommended dose is 1,500 mg/day (oral, 3X 500 mg capsules, 2 in morning) for 6 months, then 6 wk cycles of therapy.
Ciprofloxacin may or may not be taken with meals. Initially, ciprofloxacin may exacerbate some signs/symptoms (Herxheimer reactions or adverse antibiotic responses) but these are usually gone within a few wks or so. Patients report that doses of 1000 mg/day or lower are not effective in alleviating symptoms. Patients usually start feeling better with alleviation of major signs/symptoms within 4-6 wks, but in some patients signs/symptoms are not reduced until after 6 wks. Ciprofloxacin has been used for patients in which doxycycline cannot be tolerated or in some patients that no longer respond to doxycycline. In a few cases ciprofloxacin has been used simultaneously with doxycycline. Herxheimer reactions, if present, usually pass within days to a few wks; prior damage to the gastrointestinal system may require i.v. 400-500 mg X2/day (over one hr per each infusion, rapid i.v. administration is to be avoided) for 2-4 wks, then the remainder on oral antibiotic (oral doses). Virtually all
patients relapse (with major signs/symptoms) if drug is stopped at in 6-12 wk course of therapy. Additional antibiotic courses result in milder relapses after drug is discontinued. Subsequent cycles of antibiotics may require the use of doxycycline or other antibiotics. Sparfloxacin, a fluoroquinolone with better tissue penetration, can be substituted (oral dose, 400 mg/day).


Ciprofloxacin is effective against the following organisms: gram-negative bacteria (Shigella species, Citrobacter diversus, Citrobacter freundii, Escherichia coli, Klebisella pneumoniae, Haemophilus influenzae, Enterobacter species, Proteus vulgaris, Psuedomonas aeruginosa, Yersinia pestis, Vibrio cholera), Moraxella catarrhalis; gram-positive bacteria
(Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus hominis Staphylococcus aureus, Staphylococcus saprophytieus); mycoplasmas, moderately active (Mycoplasma species); others (Clostridium species, Chlamydia species, Mycobacterium tuberculosis).


Precautions: Direct sunlight is to be avoided, especially with sparfloxacin, and patients should not take floxacin and theophylline concurrently. Ciprofloxacin therapy may result in drug crystals in the urine in rare cases, and patients should be well hydrated to prevent
concentration of urine. Pregnant women and children should not use this drug due to reduction in bone and cartilage development.


Adverse Reactions: Adverse antibiotic responses resulted in discontinuing drug in ~3.5% of patients, and such reactions included nausea (5%), diarrhea (2%), vomiting (2%) abdominal pain (1.7%), headache (1.2%) and rash (1.1%). In rare cases cirprofloxacin may cause cardiovascular problems (<1%) and central nervous system (dizziness, insomnia, tremor,   confusion, convulsions and other reactions (<1%). Small numbers of patients have experienced hypersensitivity (anaphylactic) reactions which have required immediate emergency treatment. Other drugs may effect absorption and immune systems.


Azithromycin (aka Zithromax)


Azithromycin is a azalide (macrolide) antibiotic with good absorption and a serum half-life of ~68 hrs. This class of drug acts by binding to the 50S ribosomal subunit of susceptible organisms where it interferes with protein synthesis. Food decreases absorption rate, but absorption is unaffected by antacids containing magnesium, aluminum or other salts;
other drugs may affect absorption (see above).


For GWI/CFS/FMS use, the recommended dose is 500 mg/day (oral, 2X 250 mg capsules taken at once) for each 6-wk cycle of therapy. Azithromycin should not be taken with meals (1 hr before or 1 hr after). Initially, azithromycin may exacerbate some symptoms but these are usually gone within a few weeks. Patients usually start feeling better with alleviation of most major signs/symptoms within several weeks, but in some patients major symptoms are not alleviated within months. Azithromycin has been used for patients in which doxycycline cannot be tolerated or in patients that no longer respond to doxycycline. Herxheimer reactions usually pass within a few days to weeks. Virtually all patients relapse (show the same major signs/symptoms) after terminating therapy in less than 12 wks.
Additional cycles of antibiotic result in milder relapses after drug is discontinued. Azithromycin has been shown to be safe for pediatric use (10 mg/kg/day is recommended for children under 14, but see below).


Azithromycin is effective against the following organisms: gram-negative bacteria (Bordetella pertussis, Shigella species, Haemophilus influenzae, Chlamydia species, Yersinia pestis, Brucella species, Vibrio cholera); gram-positive bacteria (Streptococci group C, F, G); mycoplasmas (Mycoplasma species); others (Clostridium species, Treponema pallidum
syphilis, and Borrelia species).


Precautions: Azithromycin is principally absorbed by the liver, and caution should be exercised with patients with impaired liver function. Antacids containing magnesium, aluminum or other salts should not be taken at the same time of day with azithromycin. Other drugs can also interfere.
Macrolides plus terfenadine Seldane or astemizole Hismaral may dangeriously elevate plasma antihistamine and cause arrhythmias and increase serum theophyline levels in some patients, particularly those receiving methylated xanthine causing nausea, vomiting, seizures. Plasma levels of carbamazepine Tegretol can also be elevated, leading to  carbamazepine toxicity and nausea, vomiting, drowsiness and ataxia.


Adverse Reactions: Adverse antibiotic responses were mild to moderate in clinical trials and included diarrhea (5%), nausea (3%), abdominal pain (3%). In rare cases (<1%) azithromycin may cause cardiovascular problems (palpitations, tachycardia, chest pain) and central nervous system (dizziness, headache, vertigo), allergic (rash, photosensitivity, angioderma), fatigue and other reactions (<1%). In pediatric patients >80% of the adverse responses were gastrointestinal. In children, doses above the suggested 10 mg/kg/day have been shown to produce hearing loss in some patients.


Clarithromycin ( Biaxin)


Clarithromycin is a broad spectrum macrolide antibiotic with good absorption and serum half-life. This drug acts by binding to the 50S ribosomal subunit of susceptible organisms and interfering with protein synthesis. The drug is mostly bacterostatic but high concentrations can be bactericidal. Food decreases absorption rate, but absorption is unaffected by antacids containing magnesium, aluminum or other salts. Some drugs may interfere with absorption or depress immune systems (see above).


The recommended dose is 500-750 mg/day (oral, 2-3X 250 mg capsules, 2 taken in morning) for 6 months of therapy, then 6-wk cycles.
Clarithromycin should not be taken with meals (1 hr before or 1 hr after). Initially, clarithromycin may exacerbate some symptoms due to Herxheimer reactions and bacterial death but these are usually gone within wks. Patients usually start feeling better with alleviation of most major signs and symptoms within 1-2 wks, but in some patients major symptoms are not alleviated until after 12 wks or so. Clarithromycin has been used for
patients that do not respond or cannot tolerate doxycycline. Herxheimer reactions usually pass within days to wks. Virtually all patients relapse (show the same major signs/symptoms) when therapy is stopped within 12 wks. Additional cycles of antibiotic result in milder relapses after drug is discontinued. For children, the recommended dose is 15 mg/kg/day X2; at this dose some children have gastrointestinal problems.


Clarithromycin is effective against the following organisms: gram-negative bacteria (Neisseria gonorrhoeae, N. menigitidis, Moraxella catarrhalis, Campylobacter jejuni, Eikenella corrodens, Haemophilus ducreyi, Bordetella pertussis, Shigella species, Salmonella species, Haemophilus influenzae, Chlamydia species, Yersinia pestis, Brucella species, Vibrio cholera, Aeromonos species, E. coli, gram-positive bacteria (Streptococcus pyogenes, S. pneumeniae, anerobic Streptococci, Enterococcus faccalis, Staphlococcus aureus, S. epidermidis, Bacillus anthracis, Corynebacterium diptheriae, C. minutissimum, Listeria monocytogenes, Actinomyces israelii); mycoplasmas (Mycoplasma species, M. pneumoniae, Ureaplasma urealyticum); others (Clostridium species, Treponema pallidum syphilis,
Legionella pneumophilia, L. micdadei, Mycobacterium avium, M. chelonae, M. chelonae absessus, M. fortuitim, Rickettsia species and Borrelia species). Yeasts, fungi and viruses are resistant.


Precautions: Clarithromycin is principally absorbed by the liver, and caution should be exercised with patients with impaired liver function. Antacids containing magnesium, aluminum or other salts should not be taken at the same of day as azithromycin. Other drugs may also interfere (see above). Macrolides plus terfenadine Seldane or astemizole Hismaral may dangerously elevate plasma antihistamine and cause arrhythmias and increase serum theophyline levels in some patients, particularly those receiving methylated xanthine causing nausea, vomiting, seizures. Plasma levels of carbamazepine Tegretol can also be elevated, leading to carbamazepine toxicity and nausea, vomiting, drowsiness and ataxia.
Macrolides like clarithromycin should not be used with cyclosporin Sandimmune.


Adverse Reactions: Adverse antibiotic responses were mild to moderate in clinical trials and included diarrhea, nausea, and abdominal pain. In rare cases (<1%) azithromycin may cause cardiovascular problems (palpitations, tachycardia, chest pain) and central nervous system (dizziness, headache, vertigo), allergic (rash, photosensitivity, angioderma) and fatigue.


Clindamycin ( Cleocin, Dalacin, Lacin)


Clindamycin is a semisynthetic antibiotic made from lincomycin and is effective against severe anaerobic infections. It is primarily bacteriostatic against a wide range of Gram-positive and anaerobic pathogens, including some protozoa. It has good absorption and tissue penetration; its half-life is ~3 hrs in adults and ~2 hrs in children. Since clindamycin use can result in severe colitis even weeks after cessation of the drug, it should not be used as primary therapy. Food does not adversely affect absorption rate, but absorption is affected by antacids containing magnesium, aluminum or other salts. Some drugs may interfere with absorption or depress immune systems (see above).


The recommended dose is 600-1200 mg/day (oral, 4-8 X 150 mg capsules, in three divided doses) for 6-wk cycles of therapy. Herxheimer reactions may exacerbate signs/symptoms but these are usually gone within days-weeks. Patients usually start feeling better with alleviation of most major signs and symptoms within days-weeks, but in some patients major symptoms are not alleviated until after several weeks or so. For children, the recommended dose is 8-16 mg/kg/day divided into 3-4 doses.


Precautions: Clindamycin should not be used for patients with nonbacterial (viral, fungal) infections. Its use is associated in some patients with colitis and severe, persistent diarrhea and abdominal cramps, and when this occurs the drug should be discontinued. It must not be used with opiates or diphenoxylate with atropine Lomotil. Patients with hepatic or renal problems require dosage adjustment. Antidiarrheal drugs that reduce peristalsis, such as dipenoxylate, loperamide or opioids, should be avoided. If prolonged therapy is used, periodic liver and kidney function tests and blood counts should be performed. Clindamycin should not be used by pregnant women, and prolonged use can result in overgrowth of yeasts and other nonsusceptible microorganisms. Cholestyramine or colestipol resins bind clindamycin and should not be administered simultaneously.


Adverse Reactions: Adverse antibiotic responses were mainly diarrhea in 2-20% of cases, some severe and dangerous (colitis). Psuedomembranous colitis may develop during or several weeks after therapy. This can be serious if ignored. Other gastrointestinal effects of the drug have been reported (nausea, vomiting, esophagitis, abdominal pain or cramps), and
hypersensitivity reactions, including skin rashes occur in up to 10% of patients. Mild cases of colitis should be managed promptly with fluid, electrolyte and protein supplementation as indicated. Other effects include transient leucopenia, polyarthritis and abnormal liver function
(jaundice and hepatic damage rarely occur). Clindamycin should not be used with erythromycin. Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular drugs. Clindamycin should only be used with caution in patients receiving such drugs.


Final Comments


Recovery will be gradual not rapid, and almost all patients experience initial Herxheimer reactions that can be quite severe and can last for weeks. You will have to be patient and not abandon therapy prematurely, because few patients recover in less than one year of therapy. Do not take antibiotics at the same time of day as vitamins, minerals, supplements, etc. Vitamins and minerals should be taken 3 hrs after antibiotics to prevent interference with antibiotic uptake. Stop antibiotics if adverse reactions continue. You will experience cycles of relapse when severely physically or mentally stressed, and you should not be alarmed if some signs and symptoms occasionally return or worsen. This is not unusual.
Eventually you will be off antibiotics but you will need to continue various supplements to maintain your immune system

Source: Website: www.immed.org