Antimicrobial Effects of Antipyretics

As in ADVIL AND TYLENOL

ABSTRACT: Antipyretics are some of the most commonly used drugs. Since they are often co-administered with antimicrobial therapy, it is important to understand the interactions between these two classes of drugs. Our review is the first to summarize the antimicrobial effects of antipyretic drugs and the underlying mechanisms involved. Antipyretics can inhibit virus replication, inhibit or promote bacterial or fungal growth, alter the expression of virulence factors, change the surface hydrophobicity of microbes, influence biofilm production, affect the motility, adherence, and metabolism of pathogens, interact with the transport and release of antibiotics by leukocytes, modify the susceptibility of bacteria to antibiotics, and induce or reduce the frequency of mutations leading to antimicrobial resistance. While antipyretics may compromise the efficacy of antimicrobial therapy, they can also be beneficial, for example, in the management of biofilm-associated infections, in reducing virulence factors, in therapy of resistant pathogens, and in inducing synergistic effects. In an era where it is becoming increasingly difficult to find new antimicrobial drugs, targeting virulence factors, enhancing the efficacy of antimicrobial therapy, and reducing resistance may be important strategies.

KEYWORDS: NSAIDs, ibuprofen, acetaminophen, paracetamol, antibacterial, antimicrobial, efflux pumps

Biofilm: What is it and how to get rid of it.

~Content Source

Most bacteria are present in biofilms, not as single-acting cells

The popular image of bacteria depicts single cells floating around, releasing toxins and damaging the host. However, most bacteria do not exist in this planktonic form in the human body, but rather in sessile communities called biofilms. To form a biofilm, bacteria first adhere to a surface and then generate a polysaccharide matrix that also sequesters calcium, magnesium, iron, or whatever minerals are available.

Within a biofilm, one or more types of bacteria and/or fungi share nutrients and DNA and undergo changes to evade the immune system. Since it requires less oxygen and fewer nutrients and alters the pH at the core, the biofilm is a hostile community for most antibiotics. In addition, the biofilm forms a physical barrier that keeps most immune cells from detecting the pathogenic bacteria (12).

The current model of care misses the mark

The current model of care usually assumes acute infections caused by planktonic bacteria. However, since the vast majority of bacteria are hidden in biofilms, healthcare providers are treating most illnesses ineffectively. According to the NIH, more than 80 percent of human bacterial infections are associated with bacterial biofilm (3). While planktonic bacteria can become antibiotic resistant through gene mutations, a biofilm is often antibiotic resistant for many reasons—physical, chemical, and genetic. Treating illnesses associated with biofilms using antibiotics is an uphill battle. For example, in patients suffering from IBD, antibiotics appear initially to work, only to be followed by a “rebound,” where the symptoms again flare up, presumably due to bacteria evading the antibiotic within a biofilm (4).

According to the NIH, more than 80% of human bacterial infections are associated with biofilms.

Biofilms are hidden in the nasal passageways and GI tract

Biofilms are well-known problems associated with endoscopic procedures, vascular grafts, medical implants, dental prosthetics, and severe dermal wounds. Biofilms found along the epithelial lining of the nasal passageways and GI tract are less understood.

The GI tract is an ideal environment for bacteria, fungi, and associated biofilms because of its huge surface area and constant influx of nutrients (4). For protection, the GI epithelium is lined with viscoelastic mucus, but it can be damaged in patients with excessive inflammation, IBD, and other conditions. This creates an opportunity for bacteria to attach to the surface and begin their biofilm construction. The epithelium to which it is attached is altered and often damaged (56).

Biofilms are difficult to diagnose

A number of problems make biofilms difficult to detect.

  • First, bacteria within the biofilm are tucked away in the matrix. Therefore, swabs and cultures often show up negative. Stool samples usually do not contain the biofilm bacteria, either.
  • Second, biofilm samples within the GI tract are difficult to obtain. The procedure would require an invasive endoscope and foreknowledge of where the biofilm is located. What’s more, no current procedure to remove biofilm from the lining of the GI tract exists.
  • Third, biofilm bacteria are not easily cultured. Therefore, even if you are able to obtain a sample, it may again test negative because of the microbes’ adapted lower nutrient requirements, rendering normal culture techniques null (7).
  • Fourth, biofilms might also play a role in the healthy gut,making it difficult to distinguish between pathogenic and healthy communities (47).

Although a culture might come back negative, the microbes in a biofilm could still be pumping out toxins that cause illness. Some clinicians look for mycotoxins in the urine to identify biofilms (8), but I am not impressed by the research behind it yet. Because the bacteria sequester minerals from the host, mineral deficiency is probably associated with the presence of biofilms, although mineral deficiencies are all too common in the general population to use this alone as a diagnostic criterion.

Biofilms in the background of many diseases

The medical community is increasingly dealing with antibacterial-resistant infections, with evidence of a biofilm at work behind the scenes:

  • Up to one-third of patients with strep throat, often caused by pyogenes, do not respond to antibiotics (9). In one study, all 99 strep throat-causing bacterial isolates formed biofilms (9).
  • Ten to 20 percent of people infected with Lyme disease, caused by burgdorferi, have prolonged symptoms, possibly due to antibiotic resistance and/or biofilm presence (1011).
  • Lupus flare-ups are induced by infection, inflammation, or trauma. In this autoimmune disease, cell death by NETosis instead of apoptosis turns the immune system against itself (12). Biofilms are suspected to be involved (13).
  • For chronic rhinosinusitis (CRS), “topical antibacterial or antifungal agents have shown no benefit over placebo in random controlled trials” (14). Bacterial and fungal biofilms are consistently found in these patients’ nasal passageways (1415).
  • Antibiotic treatment of irritable bowel disease (IBD) can work for a time, but flare-ups generally continue throughout a person’s life. Biofilms have been linked to both Crohn’s disease and ulcerative colitis (161718).

Biofilms have also been implicated in chronic ear infections, chronic fatigue syndrome, multiple sclerosis, and acid reflux (41920).

Peta Cohen, a pioneer in treating autism with a biomedical and nutritional approach, has found evidence of biofilms in autistic patients. When she disrupts the biofilm in these patients, she sees a huge “offload” of heavy metals in the urine and stool. Autistic individuals often have elevated mercury and lead levels (21). Bacteria aren’t choosy about which minerals they sequester during biofilm construction, and so Dr. Cohen’s explanation is that these patients also suffer from GI biofilms loaded with mercury and other heavy metals. Her experiences are as of yet only anecdotal; a PubMed search for “autism and biofilm” yields zero results. Check out my podcast here for what I believe are underlying causes of autism.

How to treat biofilms

Antibiotic after antibiotic for IBD. Corticosteroids for CRS. If a biofilm is at work, these standard “treatments” aren’t curing anything. Clinicians instead need to break down the biofilm, attack the pathogenic bacteria within, and mop up the leftover matrix, DNA, and minerals.

Biofilm disruptors are the first course of action. Enzymes such as nattokinase and lumbrokinase have been used extensively as coatings on implants to fight biofilms (2223). Cohen’s protocol recommends half a 50mg capsule of nattokinase and half of a 20mg capsule of lumbrokinase for small children with chronic strep throat and autism. Other promising enzymes include proteases, plasmin, and streptokinase (24).

Mucolytic enzyme N-acetylcysteine (NAC) is a precursor of glutathione and an antioxidant. Effective against biofilms on prosthetic devices, in vitro biofilms, and chronic respiratory infections (25262728), NAC is recognized as a “powerful molecule” against biofilms (29).

Lauricidin (other forms: monolaurin, lauric acid, and glycerol monolaurate) is a natural surfactant found in coconut oil that helps inhibit the development of biofilms (30). In my practice, I also use it as an option for a gentler antimicrobial agent.

Colloidal silver is effective at treating topical biofilms, such as in wound dressings (31,  32). Applications in vivo are still under research. Although used successfully to treat a sheep model of bacterial sinusitis (33), colloidal silver did not show the same effectiveness in a small human trial (3435).

I recommend Klaire Labs InterFase Plus and Kirkman Biofilm Defense, two commercial products formulated to effectively disrupt biofilm.

Antimicrobial treatments follow biofilm disruptors. When necessary, I do use pharmaceutical antibiotics, but mixtures of herbal antimicrobials can be effective:

  • berberine
  • artemisinin
  • citrus seed extract
  • black walnut hulls
  • Artemisia herb
  • echinacea
  • goldenseal
  • gentian
  • fumitory
  • galbanum oil
  • oregano oil

Once the biofilm is destabilized and microbes are treated, binders help clean up the mess. EDTA disrupts biofilms and also chelates minerals in the matrix (3637). Chitosan and citrus pectin are two other options.

I can’t stress enough how important probiotics and prebiotics are in healing the gut and maintaining a healthy GI tract. Probiotics reduce pathogenic bacteria and have even been shown to disrupt the growth, adhesion, and activity of biofilms (3839). I recommend Primal Probiotics and Prebiogen or potato starch for prebiotics.

Hopefully the medical community will soon recognize biofilms as factors in many diseases and properly treat recalcitrant infections and illnesses.

What Are Fungal Fimbriae

BiofilmsAdhesions: Example – Adhesions are bands of scar-like tissue. Normally, internal tissues and organs have slippery surfaces so they can shift easily as the body moves. Adhesions cause tissues and organs to stick together. Example: They might connect the loops of the intestines to each other, to nearby organs, or to the wall of the abdomen.

Fungal fimbriae are surface appendages that were first described on the haploid cells of the smut fungus, Microbotryum violaceum. They are long (1-20 gm), narrow (7 nm) flexuous structures that have been implicated in cellular functions such as mating and pathogenesis. Since the initial description, numerous fungi from all five phyla have been shown to produce fimbriae on their extracellular surfaces.

Cell-to-cell interactions are fundamental to the processes of fungal growth and development. In particular, cell-to-cell adhesions occur during mating and pathogenesis.

Many fungi produce flexible, long (1-20 ,um), narrow (7 nm), unbranched appendages which appear similar to pili or fimbriae found on the surface of prokaryotic cells. These structures, termed fungal fimbriae, were first observed on the surface of haploid yeast-like cells of the anther smut Microbotryum violaceum (= Ustilago violacea) by Poon and Day (1974). Since their original description, fungal fimbriae have been shown to be widespread among the Mycota (Gardiner et al., 1981, 1982; Benhamou and Ouellette, 1987; Castle et al., 1992; Rghei et al., 1992; Celerin et al., 1995).

In M.violaceum, fungal fimbriae appear to be involved in cell-to-cell communication during mating before pathogenesis. Both mechanical and enzymatic removal of fimbriae from the haploid cells delays mating until fimbrial regeneration occurs (Poon and Day, 1975). In addition, mating is almost completely blocked by coating fimbriae with anti-fimbrial protein antiserum (Castle et al., 1996).

Fungal fimbriae have also been implicated as factors involved in pathogenic adhesion. Rghei et al. (1992) suggested that fimbriae are used in the initial interactions between a parasitic fungus and its host.

PDF: Fungal fimbriae are composed of collagen

Read about Filamentous Biofilm.

Filamentous Biofilm

Investigating Filamentous Growth and Biofilm/Mat Formation in Budding Yeast – Content Source NCBI/NIH

In response to nutrient limitation, budding yeast can undergo filamentous growth by differentiating into elongated chains of interconnected cells. Filamentous growth is regulated by signal transduction pathways that oversee the reorganization of cell polarity, changes to the cell cycle, and an increase in cell adhesion that occur in response to nutrient limitation. Each of these changes can be easily measured. Yeast can also grow colonially atop surfaces in a biofilm or mat of connected cells. Filamentous growth and biofilm/mat formation require cooperation among individuals; therefore, studying these responses can shed light on the origin and genetic basis of multicellular behaviors. The assays introduced here can be used to study analogous behaviors in fungal pathogens, which require filamentous growth and biofilm/mat formation for virulence.

Microbial species use diverse strategies to compete for nutrients. Being nonmotile, fungal microorganisms have developed a unique behavior, called filamentous growth, in which cells change their shape and band together in chains or filaments to scavenge for nutrients. Many fungal species can also grow in interconnected mats of cells called biofilms. The budding yeast Saccharomyces cerevisiae shows these behaviors, providing a genetically tractable system to study the pathways that control nutrient-dependent foraging. Studies on filamentous growth have provided insights into how eukaryotic cells differentiate and cooperate with each other, and how genetic pathways control fungal pathogenesis. Fungal pathogens require filamentous growth and biofilm formation for virulence.

filamentous-biofilms-nihms694247

Conclusions…

The current picture of filamentous growth is a complex one, in which multiple pathways and hundreds of targets coordinate a highly integrated response that we are only beginning to understand. Future studies of filamentous growth will aid in the understanding of the genetic basis of cell differentiation, development, and the regulation of multicellularity in eukaryotes. The assays described in the associated protocols are attractive in terms of their simplicity and potential use as teaching tools. Their versatility furthermore allows analysis of filamentous growth and biofilm formation in diverse fungal species including pathogens.