Antibiotics Recommended When Indicated for Treatment of Gulf War Illness/CFIDS/FMS

Intern. J. Medicine 1998; 1: 123-128.

by Prof. Garth L. Nicolson The Institute for Molecular Medicine, 15162 Triton Lane Huntington Beach, California 92649-1041 USA Tel: (714) 903-2900 Fax: (714) 379-2082 e-mail: gnicimm@ix.netcom.com Website: www.immed.org

Doxycycline (aka Vibramycin, Monodox, 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 hours (half-life 18-22 hours) after an oral dose of drug. Food, calcium, magnesium and antacids reduce absorption, and alcohol, phenytoin [Dilantin] or barbiturates reduce blood half-life.

For Gulf War Illness/Chronic Fatigue Syndrome/Fibromyaligia Syndrome (GWI/CFIDS/FMS) use, the recommended dose is 200-300 mg/day (oral, 2-3x100 mg capsules) for each 6 week cycle of therapy. Initially, doxycycline initially exacerbates symptoms (Herxheimer reactions or adverse antibiotic responses, such as transient fever, skin, gut discomfort, etc.) but these are usually gone within 2 weeks or so. Patients usually start feeling better with alleviation of most major signs and symptoms within 2-6 weeks, but in some patients major symptoms are not alleviated until the second 6-week course. Severe reactions or prior damage to the gastrointestinal system may require i.v. administration of 100-150 mg/day (rapid i.v. administration is to be avoided) for 2-3 weeks, then the remainder of the 6 week course should be on oral antibiotic (to avoid thrombophlebitis complications which can occur with prolonged i.v. therapy). Some react to the starch filler in the capsules and must use Doryx, a granular form of doxycycline. Virtually all patients relapse (show the same major signs and symptoms) after the end of the first and second 6-week course of therapy, and these can be run together without a pause. In a pilot study, ~85% relapsed after 2 cycles, and after 5 and 6 cycles, 27% and 11%, respectively, still relapsed after discontinuing antibiotic therapy. In some cases doxycycline has been used successfully with other antibiotics in situations where either antibiotic alone appeared to have minimal effect (for example, doxycycline in combination with ciprofloxacin).

Doxycycline is 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 [incognitis], Mycoplasma penetrans); others (Bacillus anthracis [anthrax], Clostridium species, Chlamydia species, Actinomyces species, Entamoeba species, Treponema pallidum [syphilis], Plasmodium falciparum [malaria] and Borelia species).

Precautions: Avoid direct sunlight and drink fluids liberally. Doxycycline therapy may result in overgrowth of fungi or yeast and nonsensitive microorganisms (see Other Considerations). Patients on anticoagulants may require lower anticoagulant doses. Last half of pregnancy, infancy and children under 8 years are not recommended, in the latter case due to tooth discoloration, but lower doses of doxycycline have proven to be very effective in children under 8 with GWI/CFIDS (if weight 100 lbs or less, 1-2 mg/lb divided into two doses; if is weight over 100 lbs use adult doses). 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. In case of complicating bacterial infections, a 2 week course of Augmentin (3 X 500 mg/day) should be taken between courses of doxycycline or other antibiotics. For fungal and yeast complications, please see the instructions under Other Considerations at the end of this handout.

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

Ciprofloxacin (aka 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 about 4 hours. Food delays the absorption of antibiotic (by ~2 hours) but not the total absorption; antacids containing magnesium, aluminum or other salts reduce absorption and should not be taken at the same time of day.

For GWI/CFIDS/FMS use, the recommended dose is 1500 mg/day (for oral use, 3x500 mg capsules) for each 6 week cycle of therapy. Ciprofloxacin may or may not be taken with meals. Initially, ciprofloxacin may exacerbate some symptoms symptoms (Herxheimer reactions or adverse antibiotic responses) but these are usually gone within a week or so, and some patients report that doses of 1000 mg/day or lower are not effective in alleviating GWI/CFIDS/FMS symptoms. Patients usually start feeling better with alleviation of most major signs and symptoms within 1-4 weeks, but in some patients major symptoms are not alleviated until the second 6-week course. Ciprofloxacin has been used in 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, but the usual course is one type of antibiotic alone. Herxheimer reaction, if present, usually passes within a few days to 2 weeks or so; prior damage to the gastrointestinal system may require i.v. administration of 400 mg/day (over one hour per each infusion, rapid i.v. administration is to be avoided) for 2-4 weeks, then the remainder of the 6-week course should be on oral antibiotic (oral doses). Virtually all patients relapse (show the same major signs and symptoms) after the end of the first or second 6-week course of therapy. Additional cycles of antibiotic result in milder relapses after drug is discontinued. Subsequent cycles of antibiotics may require the use of doxycycline or other antibiotics instead of ciprofloxacin.

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); gram-positive bacteria (Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus hominis, Staphylococcus saprophytieus); mycoplasmas, moderately active (Mycoplasma species); others (Clostridium species, Chlamydia species, Mycobacterium tuberculosis).

Precautions: Direct sunlight is to be avoided, and patients should not take ciprofloxacin 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 (less than 1%) and central nervous system (dizziness, insomnia, tremor, confusion, convulsions and other reactions (less than 1%). Small numbers of patients have experienced hypersensitivity (anaphylactic) reactions which have required immediate emergency treatment.

Azithromycin (aka Zithromax)

Azithromycin is a azalide (macrolide) antibiotic with good absorption and a serum half-life of 68 hours. 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.

For GWI/CFIDS/FMS use, the recommended dose is 500 mg/day (for oral use, 2x250 mg capsules) for each 6-week cycle of therapy. Azithromycin should not be taken with meals (1 hour before or 1 hour after). Initially, azithromycin may exacerbate some symptoms but these are usually gone within a week or so. Patients usually start feeling better with alleviation of most major signs and symptoms within 1-2 weeks, but in some patients major symptoms are not alleviated until the second 6 week course. Azithromycin has been used in patients in which doxycycline cannot be tolerated or in some patients that no longer respond to doxycycline. Herxheimer reactions are rare and usually passes within a few days to a week or so. Virtually all patients relapse (show the same major signs and symptoms) after the end of the first or second 6-week course of therapy. 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 Borelia sp).

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. Macrolides and terfenadine (Seldane) or astemizole (Hismaral) may dangeriously evelate 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 (less than 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 (less than 1%). In pediatric patients >80% of the adverse reponses were gastrointestinal. In children, doses above the suggested 10 mg/kg/day have been shown to produce hearing loss in some patients.

Clarithromycin (aka Biaxin)

Clarithromycin is a broad spectrum macrolide antibiotic with good absorption and serum half-life. This class of 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.

The recommended dose is 500-750 mg/day (for oral use, 2-3x250 mg capsules) for each 6-week cycle of therapy. Clarithromycin should not be taken with meals (1 hour before or 1 hour after). Initially, clarithromycin may exacerbate some symptoms due to Herxheimer reaction and bacterial death but these are usually gone within a week or so. Patients usually start feeling better with alleviation of most major signs and symptoms within 1-2 weeks, but in some patients major symptoms are not alleviated until the second 6-week course. Clarithromycin has been used in patients that do not respond to doxycycline or in patients that cannot tolerate doxycycline. Herxheimer reactions usually passes within a few days to over a week or so. Virtually all patients relapse (show the same major signs and symptoms) after the end of the first or second 6-week course of therapy. 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. Macrolides and 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 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 (less than 1%) azithromycin may cause cardiovascular problems (palpitations, tachycardia, chest pain) and central nervous system (dizziness, headache, vertigo), allergic (rash, photosensitivity, angioderma) and fatigue.

Other Important Information (see Additional Considerations...)

GWI/CFIDS/FMS patients are often low in vitamins (B, C and E) and minerals. Sublingual (under the tongue) natural B-complex vitamins (Total B, Real Life Research, Norwalk, CA) can be ordered from Vitamin Park (Irvine, CA). General vitamins plus extra C and E and general mineral supple-ments are also useful, but not at the same time of day that antibiotics are taken because minerals can affect the absorption of the antibiotics. Selenium and magnesium are two of the minerals that are needed. Some have recommend 300-500 mg/day sodium selenite for a few days, followed by lower maintenance doses. Some zinc supplementation is recommended. L- cysteine supplementation has been proposed but should not be taken at the same time as minerals. Antibiotics can result in yeast overgrowth, especially in female patients, requiring Nizoral, Diflucan, Mycelex, or anti-yeast creams for women on antibiotics. In some cases, simultaneous use of metronidazole (Flagyl, Prostat) have been used to prevent fungal and parasite overgrowth, or antifungals (Nystatin, Amphotericin B, Fluconazole) have been administered for fungal infections that can occur while on antibiotics. Lactobacillus acidophillus tablets are recommended, and 'organic' food. Caffeine should be avoided. Control of bacterial overgrowth (if necessary, page 1) between cycles of antibiotics can be done with Augmentin @3 X 500 mg/day or taken concurrently with the other antibiotics, if necessary.

A number of natural remedies, such as ginseng root, whole lemon/olive oil drink or an extract of olive leaves with antioxidants (Eden or Immunoscreen of Covina, CA), and a mixture of herbals and vitamins (Nu-Life Formula, Sophista-Care of Indian Wells, CA) have been used to boost immune systems. Although these products appear to help CFIDS/FM patients, their effectiveness in GWI/CFIDS/FM patients has not been examined. They appear to be useful after antibiotic therapy. Finally, GWI/CFIDS/FMS patients should not smoke and not drink alcohol, caffeinated products or eat refined sugar, and they should avoid pollutant exposure, especially those who are chemically sensitive. . Flying, excessive exercise and lack of sleep can make signs/symptoms worse; some exercise (don�t over do it!) and dry saunas help rid the system of contaminating chemicals.