Tuesday, May 14, 2013

FDA Findings: Xanthan Gum Primary Source of Bacterial Endotoxins

Xanthan Gum Pharmaceutical Applications

Xanthan gum, derived from the gram-negative xanthomonas campestris bacterium, is a common excipient in prescription drugs and over-the-counter medications.

Many infectious-disease professionals and the National Institutes of Health report that gram-negative bacteria may be more dangerous than the methicillin-resistant Staphylococcus aureus (MRSA) organism.

The 2008 patent application—"METHOD FOR REMOVING IMPURITIES FROM BIOPOLYMER MATERIAL"—provides the following re the endotoxins emanating from pharmaceutical-grade biopolymers such as alginate, xanthan gum and gelatine:
In pharmaceutical production, it is necessary to remove LPSs from drug product containers as even small amounts of this endotoxin will cause illness, but not disease, in humans.
LPSs are in large part responsible for the dramatic clinical manifestations of infections with pathogenic gram-negative bacteria, such as Neisseria meningitis, the pathogen that causes fulminate meningitis.
According to the FDA, xanthan gum is generally the source of this unwarranted bacterial activity.

In 2009 the Center for Drug Research and Evaluation found the following Tobradex ST microbiology issue:
Xanthan gum is the primary source of bacterial endotoxin since it is produced by bacterial fermentation. The proposed manufacturing changes were made in processing xanthan gum to achieve reduction in endotoxin level and maintaining high viscosity of the solution.
FDA standards regarding permissible endotoxin limits are not disclosed. Endotoxin data was redacted in the Tobradex ST review.

It may be circumstantial, but many pharmaceutical products containing xanthan gum are linked to necrotizing (cell death) events. Adverse events include, but are not limited to, toxic epidermal necrosis and Stevens-Johnson.

Research papers—"Bacterial Endotoxin in Human Disease"—and "Concordance of Endotoxemia with Gram-Negative Bacteremia in Patients with Gram-Negative Sepsis: a Meta-Analysis" document that endotoxins release tumor necrosis factor receptors.

Medications absent xanthan gum are also known to cause necrolysis.

The study of interaction of various pharmaceutical agents is challenging but it has been established that antibiotics can initiate endotoxin activity. This subject is discussed in "Effects of Different Types and Combinations of Antimicrobial Agents on Endotoxin Release from Gram-negative Bacteria: An In-Vitro and In-Vivo Study."

The EuroSCAR-study "Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs" and the All India Institute of Medical Sciences "Stevens Johnson syndrome, toxic epidermal necrolysis and SJS-TEN overlap: A retrospective study of causative drugs and clinical outcome" report provide further data.

Xanthomonas campestris—Xanthan Gum

Xanthomonas campestris pv. campestris is the cause of "black rot" necrotic plant disease. Fermentation of the xanthomonas campestris pathogen and its numerous molecularly-altered strains produce xanthan gum.

Xanthan gum is under FDA investigation as the presumed cause of the deadly SimplyThick infant necrotizing enterocolitis incidents.

SimplyThick® Xanthan Gum Product Health Risk Update

FDA advisories—May 2011/September 2012— warned that the SimplyThick® xanthan gum product may cause necrotizing enterocolitis in premature and post-term infants.

For unknown reasons, the SimplyThick® manufacturer expanded the health risk profile in 2013 to include all consumers with a history of necrotizing enterocolitis:
WARNING - [SimpyThick] NOT intended for use with preterm or infants under 12 months of age. Or children under the age of 12 years with a history of NEC [necrotizing enterocolitis].
Although no definitive link between NEC and SimplyThick® brand products has been found or established, in an abundance of caution, anyone at risk for or with a significant risk factor for developing NEC should not use SimplyThick® products
Gram-Negative Bacteria

Xanthomonas campestris, a gram negative bacterium, contains endotoxin (lipopolysaccharide) layers (LPSxcc). The transformation (lysis) of xanthomonas campestris to xanthan gum releases lipopolysaccharides which are known to provoke harmful immune defense mechanisms in plants and humans.

Gram-negative bacteria is mutable, often antibiotic resistant and will spark endotoxin activity. Reference: "Bacteroides: the Good, the Bad, and the Nitty-Gritty"
Clinical Microbiology Reviews 2007

Plant Pathogen Crossover

The National Institutes of Health has identified various plant pathogens and their related strains as disease prompting agents. This plant-to-human transmission phenomena is called crossover. The plant bacteria xanthonomas campestris pv. campestris is known to cause bacteremia.

The Code of Federal Regulations re Xanthan Gum Formulated Pharmaceuticals

The Code of Federal Regulations prescribe that food/pharmaceutical grade xanthan gum be extracted from non pathogenic/non toxigenic Xanthomonas campestris strains and not contain active Xanthomonas campestris cells.

Patent applications reveal that xanthan gum endotoxin-reduction methods are complex. For instance, KELTROL T [ Kelco Biopolymers] xanthan gum contains more than
one million endotoxin units per gram.

Xanthan gum was classified a Generally Recognized as Safe (GRAS) food additive in 1969 and was approved for pharmaceutical usage in 2004.

Xanthan Gum Manufacturers

Xanthan gum, manufactured in China, France, U.S. and Austria, is ubiquitous in food and pharmaceuticals. This biopolymer is classified Quantum satis. In other
words, amounts in consumer items are left to manufacturers' discretion.

Water supplies also contain the Xanthomonas campestris bacteria because industrial-grade xanthan gum is utilized by oil/gas producers as a lubricating fracking agent.

Domestic and foreign Xanthomonas campestris fermentation facilities, rarely inspected by the FDA, produce both consumer and industrial grade xanthan gum. Dual-use production sites raise quality control concerns.

The question of whether the original Xanthomonas campestris bacterium and its related mutated strains are benign excipients deserves review. Preclinical xanthan gum safety studies are dated. 

Xanthomonas Campestris Mutatations

Since the 60s interested parties have been experimenting with the Xanthomonas campestris bacteria and its progeny to achieve greater xanthan gum production.

For example, Syntro Inc. sponsored 1980s research determined that two classes of Xanthomonas campestris, mutant strain B1459, increased xanthan gum quantity but were antibiotic resistant. These findings, "Improved strains for production of xanthan gum by fermentation of Xanthomonas campestris," were published in the Journal of Industrial Microbiology (1989) 55-64.

Companies holding patents on genetically-altered Xanthomonas campestris strains are exempt from product safety trials and pre marketing constraints because the novel products are deemed substantially equivalent to the parent bacterium.

The substantially-equivalent theory is explained in "THE DOSSIER IN SUPPORT OF THE GENERALLY RECOGNIZED AS SAFE (GRAS) STATUS OF REDUCED-PYRUVATE XANTHAN GUM (RPXG) AS A FOOD INGREDIENT." This report was presented to the FDA in June 2006 by the Burdock Group on behalf of CP Kelco.

Pharmaceutical Stevens-Johnson Syndrome Associations

In defense of their products, manufacturers maintain that pharmaceutical-induced necrolysis incidents are rare. This allegation and other relevant matters are before the Supreme Court in Mutual Pharmaceutical Co. v. Bartlett (12-142). Mutual Pharmaceutical is arguing that the company should not be held responsible for the defendant's sulindac-caused toxic epidermal necrolysis illness. Sulindac, according to the product label, does not contain xanthan gum.

Rare harmful drug events can be expected to occur in > than 1/10,000 and < 1/1,000 patients.

Responsible parties acknowledge that mortality/morbidity incidence reports are subject to change because clinical trials often do not reflect reality.

For example the rotavirus (anti-diarrheal) inoculation, RotaShield (Wythe), was determined safe for infants and children until pernicious events proved otherwise.
The FDA RotaShield post-prescription advisory is:
AUG 1998: RotaShield® (Wyeth Laboratories, Inc.) Live oral rhesus-based, tetravalent, 3-dose series— Increased risk of intussusception reported following vaccination— Voluntarily withdrawn by the manufacturer in October, 1999—License revoked by FDA in November, 2002.
Xanthan Gum Excipient Pharmaceuticals and Stevens-Johnson Syndrome

The following xanthan gum formulated medications are linked to the Stevens-Johnson Syndrome. This list is not inclusive.

Rotarix—human rotavirus RIX4414 strain—xanthan gum—Stevens-Johnson Syndrome — The FDA became aware in 2010 that Rotarix and RotaTeq rotavirus vaccines contained porcine circovirus. These foreign DNA components
are not FDA-considered health risks.—"Rotarix rotavirus vaccine contaminated, officials say"

Infants'/Children's Motrin—Ibuprofen—xanthan gum—Stevens Johnson Syndrome—"Ibuprofen is safe, doctor says, despite severe injuries girl suffered after taking Motrin"—"Motrin Lawsuit: Jury Awards Girl $10 Million for Burns and Blindness"

Aldara— imiquimod—xanthan gum—Stevens-Johnson Syndrome

Lipitor—atorvastatin calcium—xanthan gum—Stevens-Johnson Syndrome

Allegra Oral Suspension—fexofenadine hydrochloride —xanthan gum—Stevens-Johnson Syndrome

Timolol GFS—timolol maleate—xanthan gum—Stevens-Johnson Syndromebacteremia

Duricef Oral Suspension—cefadroxil—xanthan gum—Stevens Johnson Syndrome

Risperdal M-Tabs—risperidone—xanthan gum—Stevens-Johnson Syndrome 1

Moxeza—moxifloxacin hydrochloride—xanthan gum—Stevens-Johnson Syndrome [xanthan gum data deleted in the FDA clinical review]

Erythromycin E.E.S. from the Saccharopolyspora erythraea strain—xanthan gum— Stevens-Johnson Syndrome

Zmax—azithromycin—xanthan gum—Stevens-Johnson Syndrome— Pfzier's warning that allergic reactions may recurr post-azithromycin exposure:
These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent exposure to antigen has not been determined.
ZEGERID Oral suspension powder—omeprazole/sodium bicarbonate—xanthan gum—Stevens-Johnson Syndrome

TAMIFLU oral suspension—oseltamivir phosphate—xanthan gum—Stevens-Johnson Syndrome — "The Myth of Tamiflu: 5 Things You Should Know"— Forbes

BIAXIN Granules for oral suspension—Clarithromycin—xanthan gum—Stevens-Johnson Syndrome

AUGMENTIN XR—amoxicillin/clavulanate potassium—xanthan gum—Stevens-Johnson Syndrome

VIOXX Oral Suspension —rofecoxib—xanthan gum—Stevens-Johnson Syndrome—Vioxx has been attributed to 27,000 heart attacks or sudden cardiac deaths while prescribed 1999-2003—Vigor Study

MEGACE —megestrol acetate—xanthan gum—Stevens-Johnson Syndrome —no mutagenesis studies conducted— "New Jersey pharmaceutical company pleads guilty to illegal marketing" of Megace to elder care facility physicians.

Cedax (ceftibuten) Cedax Oral Suspension—xanthan gum—Stevens-Johnson SyndromeFDA Cedax False Advertising Warning Letter

Tegretol Oral Suspension— carbamazepine—xanthan gum— Stevens-Johnson Syndrome

Xanthan Gum Endotoxins

It is disconcerting to learn that contrary to the information published in the Code of Federal Regulations, xanthan gum endotoxins are permitted in pharmaceutical products.

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