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Bacteriophage

A bacteriophage, also known informally as a phage , is a virus that infects and replicates within bacteria and archaea. The term was derived from "bacteria" and the Greek (phagein), meaning "to devour". Bacteriophages are composed of proteins that encapsulate a DNA or RNA genome, and may have structures that are either simple or elaborate. Their genomes may encode as few as four genes (e.g. MS2) and as many as hundreds of genes. Phages replicate within the bacterium following the injection of their genome into its cytoplasm.

Bacteriophages are among the most common and diverse entities in the biosphere. Bacteriophages are ubiquitous viruses, found wherever bacteria exist. It is estimated there are more than 1031 bacteriophages on the planet, more than every other organism on Earth, including bacteria, combined. Viruses are the most abundant biological entity in the water column of the world's oceans, and the second largest component of biomass after prokaryotes, where up to 9x108 virions per millilitre have been found in microbial mats at the surface, and up to 70% of marine bacteria may be infected by bacteriophages.

Bacteriophages were used from the 1920s as an alternative to antibiotics in the former Soviet Union and Central Europe, as well as in France. They are seen as a possible therapy against multi-drug-resistant strains of many bacteria (see phage therapy).

Bacteriophages are known to interact with the immune system both indirectly via bacterial expression of phage-encoded proteins and directly by influencing innate immunity and bacterial clearance. Phage–host interactions are becoming increasingly important areas of research.

Classification
Bacteriophages occur abundantly in the biosphere, with different genomes and lifestyles. Phages are classified by the International Committee on Taxonomy of Viruses (ICTV) according to morphology and nucleic acid.

It has been suggested that members of Picobirnaviridae infect bacteria, but not mammals.

There are also many unassigned genera of the class Leviviricetes: Chimpavirus, Hohglivirus, Mahrahvirus, Meihzavirus, Nicedsevirus, Sculuvirus, Skrubnovirus, Tetipavirus and Winunavirus containing linear ssRNA genomes and the unassigned genus Lilyvirus of the order Caudovirales containing a linear dsDNA genome.

History

In 1896, Ernest Hanbury Hankin reported that something in the waters of the Ganges and Yamuna rivers in India had a marked antibacterial action against cholera and it could pass through a very fine porcelain filter. In 1915, British bacteriologist Frederick Twort, superintendent of the Brown Institution of London, discovered a small agent that infected and killed bacteria. He believed the agent must be one of the following:
 * 1) a stage in the life cycle of the bacteria
 * 2) an enzyme produced by the bacteria themselves, or
 * 3) a virus that grew on and destroyed the bacteria

Twort's research was interrupted by the onset of World War I, as well as a shortage of funding and the discoveries of antibiotics.

Independently, French-Canadian microbiologist Félix d'Hérelle, working at the Pasteur Institute in Paris, announced on 3 September 1917 that he had discovered "an invisible, antagonistic microbe of the dysentery bacillus". For d'Hérelle, there was no question as to the nature of his discovery: "In a flash I had understood: what caused my clear spots was in fact an invisible microbe... a virus parasitic on bacteria." D'Hérelle called the virus a bacteriophage, a bacteria-eater (from the Greek phagein, meaning "to devour"). He also recorded a dramatic account of a man suffering from dysentery who was restored to good health by the bacteriophages. It was d'Hérelle who conducted much research into bacteriophages and introduced the concept of phage therapy. In 1919, in Paris, France, d'Hérelle conducted the first clinical application of a bacteriophage, with the first reported use in the United States being in 1922.

Nobel prizes awarded for phage research
In 1969, Max Delbrück, Alfred Hershey, and Salvador Luria were awarded the Nobel Prize in Physiology or Medicine for their discoveries of the replication of viruses and their genetic structure. Specifically the work of Hershey, as contributor to the Hershey–Chase experiment in 1952, provided convincing evidence that DNA, not protein, was the genetic material of life. Delbrück and Luria carried out the Luria–Delbrück experiment which demonstrated statistically that mutations in bacteria occur randomly and thus follow Darwinian rather than Lamarckian principles.

Phage therapy

Phages were discovered to be antibacterial agents and were used in the former Soviet Republic of Georgia (pioneered there by Giorgi Eliava with help from the co-discoverer of bacteriophages, Félix d'Hérelle) during the 1920s and 1930s for treating bacterial infections.

D'Herelle "quickly learned that bacteriophages are found wherever bacteria thrive: in sewers, in rivers that catch waste runoff from pipes, and in the stools of convalescent patients."

They had widespread use, including treatment of soldiers in the Red Army. However, they were abandoned for general use in the West for several reasons:
 * Antibiotics were discovered and marketed widely. They were easier to make, store, and prescribe.
 * Medical trials of phages were carried out, but a basic lack of understanding of phages raised questions about the validity of these trials.
 * Publication of research in the Soviet Union was mainly in the Russian or Georgian languages and for many years was not followed internationally.
 * The Soviet technology was widely discouraged and in some cases illegal due to the infamous red scare.

The use of phages has continued since the end of the Cold War in Russia, Georgia, and elsewhere in Central and Eastern Europe. The first regulated, randomized, double-blind clinical trial was reported in the Journal of Wound Care in June 2009, which evaluated the safety and efficacy of a bacteriophage cocktail to treat infected venous ulcers of the leg in human patients. The FDA approved the study as a Phase I clinical trial. The study's results demonstrated the safety of therapeutic application of bacteriophages, but did not show efficacy. The authors explained that the use of certain chemicals that are part of standard wound care (e.g. lactoferrin or silver) may have interfered with bacteriophage viability. Shortly after that, another controlled clinical trial in Western Europe (treatment of ear infections caused by Pseudomonas aeruginosa) was reported in the journal Clinical Otolaryngology in August 2009. The study concludes that bacteriophage preparations were safe and effective for treatment of chronic ear infections in humans. Additionally, there have been numerous animal and other experimental clinical trials evaluating the efficacy of bacteriophages for various diseases, such as infected burns and wounds, and cystic fibrosis-associated lung infections, among others. On the other hand, phages of Inoviridae have been shown to complicate biofilms involved in pneumonia and cystic fibrosis and to shelter the bacteria from drugs meant to eradicate disease, thus promoting persistent infection.

Meanwhile, bacteriophage researchers have been developing engineered viruses to overcome antibiotic resistance, and engineering the phage genes responsible for coding enzymes that degrade the biofilm matrix, phage structural proteins, and the enzymes responsible for lysis of the bacterial cell wall. There have been results showing that T4 phages that are small in size and short-tailed can be helpful in detecting E. coli in the human body.

Therapeutic efficacy of a phage cocktail was evaluated in a mouse model with nasal infection of multi-drug-resistant (MDR) A. baumannii. Mice treated with the phage cocktail showed a 2.3-fold higher survival rate compared to those untreated at seven days post-infection.

In 2017, a 68-year-old diabetic patient with necrotizing pancreatitis complicated by a pseudocyst infected with MDR A. baumannii strains was being treated with a cocktail of Azithromycin, Rifampicin, and Colistin for 4 months without results and overall rapidly declining health.

Because discussion had begun of the clinical futility of further treatment, an Emergency Investigational New Drug (eIND) was filed as a last effort to at the very least gain valuable medical data from the situation, and approved, so he was subjected to phage therapy using a percutaneously (PC) injected cocktail containing nine different phages that had been identified as effective against the primary infection strain by rapid isolation and testing techniques (a process which took under a day). This proved effective for a very brief period, although the patient remained unresponsive and his health continued to worsen; soon isolates of a strain of A. baumannii were being collected from drainage of the cyst that showed resistance to this cocktail, and a second cocktail which was tested to be effective against this new strain was added, this time by intravenous (IV) injection as it had become clear that the infection was more pervasive than originally thought.

Once on the combination of the IV and PC therapy the patient's downward clinical trajectory reversed, and within two days he had awoken from his coma and become responsive. As his immune system began to function he had to be temporarily removed from the cocktail because his fever was spiking to over 104 F, but after two days the phage cocktails were re-introduced at levels he was able to tolerate. The original three-antibiotic cocktail was replaced by minocycline after the bacterial strain was found not to be resistant to this and he rapidly regained full lucidity, although he was not discharged from the hospital until roughly 145 days after phage therapy began. Towards the end of the therapy it was discovered that the bacteria had become resistant to both of the original phage cocktails, but they were continued because they seemed to be preventing minocycline resistance from developing in the bacterial samples collected so were having a useful synergistic effect.

Food industry
Phages have increasingly been used to safen food products and to forestall spoilage bacteria. Since 2006, the United States Food and Drug Administration (FDA) and United States Department of Agriculture (USDA) have approved several bacteriophage products. LMP-102 (Intralytix) was approved for treating ready-to-eat (RTE) poultry and meat products. In that same year, the FDA approved LISTEX (developed and produced by Micreos) using bacteriophages on cheese to kill Listeria monocytogenes bacteria, in order to give them generally recognized as safe (GRAS) status. In July 2007, the same bacteriophage were approved for use on all food products. In 2011 USDA confirmed that LISTEX is a clean label processing aid and is included in USDA. Research in the field of food safety is continuing to see if lytic phages are a viable option to control other food-borne pathogens in various food products.

Water indicators
Bacteriophages, including those specific to Escherichia coli, have been employed as indicators of fecal contamination in water sources. Due to their shared structural and biological characteristics, coliphages can serve as proxies for viral fecal contamination and the presence of pathogenic viruses such as rotavirus, norovirus, and HAV. Research conducted on wastewater treatment systems has revealed significant disparities in the behavior of coliphages compared to fecal coliforms, demonstrating a distinct correlation with the recovery of pathogenic viruses at the treatment's conclusion. Establishing a secure discharge threshold, studies have determined that discharges below 3000 PFU/100 mL are considered safe in terms of limiting the release of pathogenic viruses.

Diagnostics
In 2011, the FDA cleared the first bacteriophage-based product for in vitro diagnostic use. The KeyPath MRSA/MSSA Blood Culture Test uses a cocktail of bacteriophage to detect Staphylococcus aureus in positive blood cultures and determine methicillin resistance or susceptibility. The test returns results in about five hours, compared to two to three days for standard microbial identification and susceptibility test methods. It was the first accelerated antibiotic-susceptibility test approved by the FDA.

Counteracting bioweapons and toxins
Government agencies in the West have for several years been looking to Georgia and the former Soviet Union for help with exploiting phages for counteracting bioweapons and toxins, such as anthrax and botulism. Developments are continuing among research groups in the U.S. Other uses include spray application in horticulture for protecting plants and vegetable produce from decay and the spread of bacterial disease. Other applications for bacteriophages are as biocides for environmental surfaces, e.g., in hospitals, and as preventative treatments for catheters and medical devices before use in clinical settings. The technology for phages to be applied to dry surfaces, e.g., uniforms, curtains, or even sutures for surgery now exists. Clinical trials reported in Clinical Otolaryngology show success in veterinary treatment of pet dogs with otitis.

Bacterium sensing and identification
The sensing of phage-triggered ion cascades (SEPTIC) bacterium sensing and identification method uses the ion emission and its dynamics during phage infection and offers high specificity and speed for detection.

Phage display
Phage display is a different use of phages involving a library of phages with a variable peptide linked to a surface protein. Each phage genome encodes the variant of the protein displayed on its surface (hence the name), providing a link between the peptide variant and its encoding gene. Variant phages from the library may be selected through their binding affinity to an immobilized molecule (e.g., botulism toxin) to neutralize it. The bound, selected phages can be multiplied by reinfecting a susceptible bacterial strain, thus allowing them to retrieve the peptides encoded in them for further study.

Antimicrobial drug discovery
Phage proteins often have antimicrobial activity and may serve as leads for peptidomimetics, i.e. drugs that mimic peptides. Phage-ligand technology makes use of phage proteins for various applications, such as binding of bacteria and bacterial components (e.g. endotoxin) and lysis of bacteria.

Basic research
Bacteriophages are important model organisms for studying principles of evolution and ecology.

Dairy industry
Bacteriophages present in the environment can cause cheese to not ferment. In order to avoid this, mixed-strain starter cultures and culture rotation regimes can be used. Genetic engineering of culture microbes – especially Lactococcus lactis and Streptococcus thermophilus – have been studied for genetic analysis and modification to improve phage resistance. This has especially focused on plasmid and recombinant chromosomal modifications.

Some research has focused on the potential of bacteriophages as antimicrobial against foodborne pathogens and biofilm formation within the dairy industry. As the spread of antibiotic resistance is a main concern within the dairy industry, phages can serve as a promising alternative.

Replication
The life cycle of bacteriophages tends to be either a lytic cycle or a lysogenic cycle. In addition, some phages display pseudolysogenic behaviors.

With lytic phages such as the T4 phage, bacterial cells are broken open (lysed) and destroyed after immediate replication of the virion. As soon as the cell is destroyed, the phage progeny can find new hosts to infect. Lytic phages are more suitable for phage therapy. Some lytic phages undergo a phenomenon known as lysis inhibition, where completed phage progeny will not immediately lyse out of the cell if extracellular phage concentrations are high. This mechanism is not identical to that of the temperate phage going dormant and usually is temporary.

In contrast, the lysogenic cycle does not result in immediate lysing of the host cell. Those phages able to undergo lysogeny are known as temperate phages. Their viral genome will integrate with host DNA and replicate along with it, relatively harmlessly, or may even become established as a plasmid. The virus remains dormant until host conditions deteriorate, perhaps due to depletion of nutrients, then, the endogenous phages (known as prophages) become active. At this point they initiate the reproductive cycle, resulting in lysis of the host cell. As the lysogenic cycle allows the host cell to continue to survive and reproduce, the virus is replicated in all offspring of the cell. An example of a bacteriophage known to follow the lysogenic cycle and the lytic cycle is the phage lambda of E. coli.

Sometimes prophages may provide benefits to the host bacterium while they are dormant by adding new functions to the bacterial genome, in a phenomenon called lysogenic conversion. Examples are the conversion of harmless strains of Corynebacterium diphtheriae or Vibrio cholerae by bacteriophages to highly virulent ones that cause diphtheria or cholera, respectively. Strategies to combat certain bacterial infections by targeting these toxin-encoding prophages have been proposed.

Attachment and penetration

Bacterial cells are protected by a cell wall of polysaccharides, which are important virulence factors protecting bacterial cells against both immune host defenses and antibiotics. Host growth conditions also influence the ability of the phage to attach and invade them. As phage virions do not move independently, they must rely on random encounters with the correct receptors when in solution, such as blood, lymphatic circulation, irrigation, soil water, etc.

Myovirus bacteriophages use a hypodermic syringe-like motion to inject their genetic material into the cell. After contacting the appropriate receptor, the tail fibers flex to bring the base plate closer to the surface of the cell. This is known as reversible binding. Once attached completely, irreversible binding is initiated and the tail contracts, possibly with the help of ATP present in the tail, injecting genetic material through the bacterial membrane. The injection is accomplished through a sort of bending motion in the shaft by going to the side, contracting closer to the cell and pushing back up. Podoviruses lack an elongated tail sheath like that of a myovirus, so instead, they use their small, tooth-like tail fibers enzymatically to degrade a portion of the cell membrane before inserting their genetic material.

Synthesis of proteins and nucleic acid
Within minutes, bacterial ribosomes start translating viral mRNA into protein. For RNA-based phages, RNA replicase is synthesized early in the process. Proteins modify the bacterial RNA polymerase so it preferentially transcribes viral mRNA. The host's normal synthesis of proteins and nucleic acids is disrupted, and it is forced to manufacture viral products instead. These products go on to become part of new virions within the cell, helper proteins that contribute to the assemblage of new virions, or proteins involved in cell lysis. In 1972, Walter Fiers (University of Ghent, Belgium) was the first to establish the complete nucleotide sequence of a gene and in 1976, of the viral genome of bacteriophage MS2. Some dsDNA bacteriophages encode ribosomal proteins, which are thought to modulate protein translation during phage infection.

Virion assembly
In the case of the T4 phage, the construction of new virus particles involves the assistance of helper proteins that act catalytically during phage morphogenesis. The base plates are assembled first, with the tails being built upon them afterward. The head capsids, constructed separately, will spontaneously assemble with the tails. During assembly of the phage T4 virion, the morphogenetic proteins encoded by the phage genes interact with each other in a characteristic sequence. Maintaining an appropriate balance in the amounts of each of these proteins produced during viral infection appears to be critical for normal phage T4 morphogenesis. The DNA is packed efficiently within the heads. The whole process takes about 15 minutes.

Release of virions
Phages may be released via cell lysis, by extrusion, or, in a few cases, by budding. Lysis, by tailed phages, is achieved by an enzyme called endolysin, which attacks and breaks down the cell wall peptidoglycan. An altogether different phage type, the filamentous phage, makes the host cell continually secrete new virus particles. Released virions are described as free, and, unless defective, are capable of infecting a new bacterium. Budding is associated with certain Mycoplasma phages. In contrast to virion release, phages displaying a lysogenic cycle do not kill the host and instead become long-term residents as prophages.

Communication
Research in 2017 revealed that the bacteriophage Φ3T makes a short viral protein that signals other bacteriophages to lie dormant instead of killing the host bacterium. Arbitrium is the name given to this protein by the researchers who discovered it.

Genome structure
Given the millions of different phages in the environment, phage genomes come in a variety of forms and sizes. RNA phages such as MS2 have the smallest genomes, with only a few kilobases. However, some DNA phages such as T4 may have large genomes with hundreds of genes; the size and shape of the capsid varies along with the size of the genome. The largest bacteriophage genomes reach a size of 735 kb. Bacteriophage genomes can be highly mosaic, i.e. the genome of many phage species appear to be composed of numerous individual modules. These modules may be found in other phage species in different arrangements. Mycobacteriophages, bacteriophages with mycobacterial hosts, have provided excellent examples of this mosaicism. In these mycobacteriophages, genetic assortment may be the result of repeated instances of site-specific recombination and illegitimate recombination (the result of phage genome acquisition of bacterial host genetic sequences). Evolutionary mechanisms shaping the genomes of bacterial viruses vary between different families and depend upon the type of the nucleic acid, characteristics of the virion structure, as well as the mode of the viral life cycle. Some marine roseobacter phages contain deoxyuridine (dU) instead of deoxythymidine (dT) in their genomic DNA. There is some evidence that this unusual component is a mechanism to evade bacterial defense mechanisms such as restriction endonucleases and CRISPR/Cas systems which evolved to recognize and cleave sequences within invading phages, thereby inactivating them. Other phages have long been known to use unusual nucleotides. In 1963, Takahashi and Marmur identified a Bacillus phage that has dU substituting dT in its genome, and in 1977, Kirnos et al. identified a cyanophage containing 2-aminoadenine (Z) instead of adenine (A).

Systems biology
The field of systems biology investigates the complex networks of interactions within an organism, usually using computational tools and modeling. For example, a phage genome that enters into a bacterial host cell may express hundreds of phage proteins which will affect the expression of numerous host genes or the host's metabolism. All of these complex interactions can be described and simulated in computer models.

For instance, infection of Pseudomonas aeruginosa by the temperate phage PaP3 changed the expression of 38% (2160/5633) of its host's genes. Many of these effects are probably indirect, hence the challenge becomes to identify the direct interactions among bacteria and phage.

Several attempts have been made to map protein–protein interactions among phage and their host. For instance, bacteriophage lambda was found to interact with its host, E. coli, by dozens of interactions. Again, the significance of many of these interactions remains unclear, but these studies suggest that there most likely are several key interactions and many indirect interactions whose role remains uncharacterized.

Host resistance
Bacteriophages are a major threat to bacteria and prokaryotes have evolved numerous mechanisms to block infection or to block the replication of bacteriophages within host cells. The CRISPR system is one such mechanism as are retrons and the anti-toxin system encoded by them. The Thoeris defense system is known to deploy a unique strategy for bacterial antiphage resistance via NAD+ degradation.

Bacteriophage–host symbiosis
Temperate phages are bacteriophages that integrate their genetic material into the host as extrachromosomal episomes or as a prophage during a lysogenic cycle. Some temperate phages can confer fitness advantages to their host in numerous ways, including giving antibiotic resistance through the transfer or introduction of antibiotic resistance genes (ARGs), protecting hosts from phagocytosis, protecting hosts from secondary infection through superinfection exclusion,   enhancing host pathogenicity, or enhancing bacterial metabolism or growth. Bacteriophage–host symbiosis may benefit bacteria by providing selective advantages while passively replicating the phage genome.

In the environment
Metagenomics has allowed the in-water detection of bacteriophages that was not possible previously.

Also, bacteriophages have been used in hydrological tracing and modelling in river systems, especially where surface water and groundwater interactions occur. The use of phages is preferred to the more conventional dye marker because they are significantly less absorbed when passing through ground waters and they are readily detected at very low concentrations. Non-polluted water may contain approximately 2×108 bacteriophages per ml.

Bacteriophages are thought to contribute extensively to horizontal gene transfer in natural environments, principally via transduction, but also via transformation. Metagenomics-based studies also have revealed that viromes from a variety of environments harbor antibiotic-resistance genes, including those that could confer multidrug resistance.

Recent findings have mapped the complex and intertwined arsenal of anti-phage defense tools in environmental bacteria.

In humans
Although phages do not infect humans, there are countless phage particles in the human body, given our extensive microbiome. Our phage population has been called the human phageome, including the "healthy gut phageome" (HGP) and the "diseased human phageome" (DHP). The active phageome of a healthy human (i.e., actively replicating as opposed to nonreplicating, integrated prophage) has been estimated to comprise dozens to thousands of different viruses. There is evidence that bacteriophages and bacteria interact in the human gut microbiome both antagonistically and beneficially.

Preliminary studies have indicated that common bacteriophages are found in 62% of healthy individuals on average, while their prevalence was reduced by 42% and 54% on average in patients with ulcerative colitis (UC) and Crohn's disease (CD). Abundance of phages may also decline in the elderly.

The most common phages in the human intestine, found worldwide, are crAssphages. CrAssphages are transmitted from mother to child soon after birth, and there is some evidence suggesting that they may be transmitted locally. Each person develops their own unique crAssphage clusters. CrAss-like phages also may be present in primates besides humans.

Commonly studied bacteriophages
Among the countless phages, only a few have been studied in detail, including some historically important phage that were discovered in the early days of microbial genetics. These, especially the T-phage, helped to discover important principles of gene structure and function.

 * 186 phage
 * λ phage
 * Φ6 phage
 * Φ29 phage
 * ΦX174
 * Bacteriophage φCb5
 * G4 phage
 * M13 phage
 * MS2 phage (23–28 nm in size)
 * N4 phage
 * P1 phage
 * P2 phage
 * P4 phage
 * R17 phage
 * T2 phage
 * T4 phage (169 kbp genome, 200 nm long )
 * T7 phage
 * T12 phage

Bacteriophage databases and resources

 * Phagesdb
 * Phagescope

title: Bacteriophage


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Bactericide

A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria. Bactericides are disinfectants, antiseptics, or antibiotics. However, material surfaces can also have bactericidal properties based solely on their physical surface structure, as for example biomaterials like insect wings.

Disinfectants
The most used disinfectants are those applying
 * active chlorine (i.e., hypochlorites, chloramines, dichloroisocyanurate and trichloroisocyanurate, wet chlorine, chlorine dioxide, etc.),
 * active oxygen (peroxides, such as peracetic acid, potassium persulfate, sodium perborate, sodium percarbonate, and urea perhydrate),
 * iodine (povidone-iodine, Lugol's solution, iodine tincture, iodinated nonionic surfactants),
 * concentrated alcohols (mainly ethanol, 1-propanol, called also n-propanol and 2-propanol, called isopropanol and mixtures thereof; further, 2-phenoxyethanol and 1- and 2-phenoxypropanols are used),
 * phenolic substances (such as phenol (also called "carbolic acid"), cresols such as thymol, halogenated (chlorinated, brominated) phenols, such as hexachlorophene, triclosan, trichlorophenol, tribromophenol, pentachlorophenol, salts and isomers thereof),
 * cationic surfactants, such as some quaternary ammonium cations (such as benzalkonium chloride, cetyl trimethylammonium bromide or chloride, didecyldimethylammonium chloride, cetylpyridinium chloride, benzethonium chloride) and others, non-quaternary compounds, such as chlorhexidine, glucoprotamine, octenidine dihydrochloride etc.),
 * strong oxidizers, such as ozone and permanganate solutions;
 * heavy metals and their salts, such as colloidal silver, silver nitrate, mercury chloride, phenylmercury salts, copper sulfate, copper oxide-chloride etc. Heavy metals and their salts are the most toxic and environment-hazardous bactericides and therefore their use is strongly discouraged or prohibited
 * strong acids (phosphoric, nitric, sulfuric, amidosulfuric, toluenesulfonic acids), pH < 1, and
 * alkalis (sodium, potassium, calcium hydroxides), such as of pH > 13, particularly under elevated temperature (above 60 °C), kills bacteria.

Antiseptics
As antiseptics (i.e., germicide agents that can be used on human or animal body, skin, mucosae, wounds and the like), few of the above-mentioned disinfectants can be used, under proper conditions (mainly concentration, pH, temperature and toxicity toward humans and animals). Among them, some important are Others are generally not applicable as safe antiseptics, either because of their corrosive or toxic nature.
 * properly diluted chlorine preparations (f.e. Dakin's solution, 0.5% sodium or potassium hypochlorite solution, pH-adjusted to pH 7–8, or 0.5–1% solution of sodium benzenesulfochloramide (chloramine B)), some
 * iodine preparations, such as iodopovidone in various galenics (ointment, solutions, wound plasters), in the past also Lugol's solution,
 * peroxides such as urea perhydrate solutions and pH-buffered 0.1 – 0.25% peracetic acid solutions,
 * alcohols with or without antiseptic additives, used mainly for skin antisepsis,
 * weak organic acids such as sorbic acid, benzoic acid, lactic acid and salicylic acid
 * some phenolic compounds, such as hexachlorophene, triclosan and Dibromol, and
 * cationic surfactants, such as 0.05–0.5% benzalkonium, 0.5–4% chlorhexidine, 0.1–2% octenidine solutions.

Antibiotics
Bactericidal antibiotics kill bacteria; bacteriostatic antibiotics slow their growth or reproduction.

Bactericidal antibiotics that inhibit cell wall synthesis: the beta-lactam antibiotics (penicillin derivatives (penams), cephalosporins (cephems), monobactams, and carbapenems) and vancomycin.

Also bactericidal are daptomycin, fluoroquinolones, metronidazole, nitrofurantoin, co-trimoxazole, telithromycin.

Aminoglycosidic antibiotics are usually considered bactericidal, although they may be bacteriostatic with some organisms.

As of 2004, the distinction between bactericidal and bacteriostatic agents appeared to be clear according to the basic/clinical definition, but this only applies under strict laboratory conditions and it is important to distinguish microbiological and clinical definitions. The distinction is more arbitrary when agents are categorized in clinical situations. The supposed superiority of bactericidal agents over bacteriostatic agents is of little relevance when treating the vast majority of infections with gram-positive bacteria, particularly in patients with uncomplicated infections and noncompromised immune systems. Bacteriostatic agents have been effectively used for treatment that are considered to require bactericidal activity. Furthermore, some broad classes of antibacterial agents considered bacteriostatic can exhibit bactericidal activity against some bacteria on the basis of in vitro determination of MBC/MIC values. At high concentrations, bacteriostatic agents are often bactericidal against some susceptible organisms. The ultimate guide to treatment of any infection must be clinical outcome.

Surfaces
Material surfaces can exhibit bactericidal properties because of their crystallographic surface structure.

Somewhere in the mid-2000s it was shown that metallic nanoparticles can kill bacteria. The effect of a silver nanoparticle for example depends on its size with a preferential diameter of about 1–10 nm to interact with bacteria.

In 2013, cicada wings were found to have a selective anti-gram-negative bactericidal effect based on their physical surface structure. Mechanical deformation of the more or less rigid nanopillars found on the wing releases energy, striking and killing bacteria within minutes, hence called a mechano-bactericidal effect.

In 2020 researchers combined cationic polymer adsorption and femtosecond laser surface structuring to generate a bactericidal effect against both gram-positive Staphylococcus aureus and gram-negative Escherichia coli bacteria on borosilicate glass surfaces, providing a practical platform for the study of the bacteria-surface interaction.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Bactericide


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Brion Gysin

Brion Gysin (19 January 1916 – 13 July 1986) was a British-Canadian painter, writer, sound poet, performance artist and inventor of experimental devices.

He is best known for his use of the cut-up technique, alongside his close friend, the novelist William S. Burroughs. With the engineer Ian Sommerville he also invented the Dreamachine, a flicker device designed as an art object to be viewed with the eyes closed. It was in painting and drawing, however, that Gysin devoted his greatest efforts, creating calligraphic works inspired by cursive Japanese "grass" script and Arabic script. Burroughs later stated that "Brion Gysin was the only man I ever respected."

Early years
John Clifford Brian Gysin was born at the Canadian military hospital in Taplow, Buckinghamshire, England. His mother, Stella Margaret Martin, was a Canadian from Deseronto, Ontario. His father, Leonard Gysin, a captain with the Canadian Expeditionary Force, was killed in action eight months after his son's birth. Stella returned to Canada and settled in Edmonton, Alberta where her son became "the only Catholic day-boy at an Anglican boarding school". Leaving that school at the age of fifteen, Gysin was sent next to Downside School in Stratton-on-the-Fosse, near Bath in England, a prestigious school for boys run by Benedictine monks. Despite attending both Anglican and Roman Catholic schools, Gysin was already an atheist when he left St Joseph's.

Surrealism
In 1934, he moved to Paris to study La Civilisation Française, an open course given at the Sorbonne where he made literary and artistic contacts through Marie Berthe Aurenche, Max Ernst's second wife. He joined the Surrealist Group and began associating with Valentine Hugo, Leonor Fini, Salvador Dalí, Picasso and Dora Maar. A year later, he had his first exhibition at the Galérie Quatre Chemins in Paris with Ernst, Picasso, Hans Arp, Hans Bellmer, Victor Brauner, Giorgio de Chirico, Dalí, Marcel Duchamp, René Magritte, Man Ray and Yves Tanguy. On the day of the preview, however, he was expelled from the Surrealist Group by André Breton, who ordered the poet Paul Éluard to take down his pictures. Gysin was 19 years old. His biographer, John Geiger, suggests the arbitrary expulsion "had the effect of a curse. Years later, he blamed other failures on the Breton incident. It gave rise to conspiracy theories about the powerful interests who seek control of the art world. He gave various explanations for the expulsion, the more elaborate involving 'insubordination' or lèse majesté towards Breton".

After World War II
After serving in the U.S. army during World War II, Gysin published a biography of Josiah "Uncle Tom" Henson titled, To Master, a Long Goodnight: The History of Slavery in Canada (1946). A gifted draughtsman, he took an 18-month course learning the Japanese language (including calligraphy) that would greatly influence his artwork. In 1949, he was among the first Fulbright Fellows. His goal was to research, at the University of Bordeaux and in the Archivo de Indias in Seville, Spain, the history of slavery, a project that he later abandoned. He moved to Tangier, Morocco, after visiting the city with novelist and composer Paul Bowles in 1950. In 1952/3 he met the travel writer and sexual adventurer Anne Cumming and they remained friends until his death.

Morocco and the Beat Hotel
In 1954 in Tangier, Gysin opened a restaurant called The 1001 Nights, with his friend Mohamed Hamri, who was the cook. Gysin hired the Master Musicians of Jajouka from the village of Jajouka to perform alongside entertainment that included acrobats, a dancing boy and fire eaters. The musicians performed there for an international clientele that included William S. Burroughs. Gysin lost the business in 1958, and the restaurant closed permanently. That same year, Gysin returned to Paris, taking lodgings in a flophouse located at 9 rue Gît-le-Cœur that would become famous as the Beat Hotel. Working on a drawing, he discovered a Dada technique by accident:

William Burroughs and I first went into techniques of writing, together, back in room No. 15 of the Beat Hotel during the cold Paris spring of 1958... Burroughs was more intent on Scotch-taping his photos together into one great continuum on the wall, where scenes faded and slipped into one another, than occupied with editing the monster manuscript... Naked Lunch appeared and Burroughs disappeared. He kicked his habit with Apomorphine and flew off to London to see Dr Dent, who had first turned him on to the cure. While cutting a mount for a drawing in room No. 15, I sliced through a pile of newspapers with my Stanley blade and thought of what I had said to Burroughs some six months earlier about the necessity for turning painters' techniques directly into writing. I picked up the raw words and began to piece together texts that later appeared as "First Cut-Ups" in Minutes to Go (Two Cities, Paris 1960).

When Burroughs returned from London in September 1959, Gysin not only shared his discovery with his friend but the new techniques he had developed for it. Burroughs then put the techniques to use while completing Naked Lunch and the experiment dramatically changed the landscape of American literature. Gysin helped Burroughs with the editing of several of his novels including Interzone, and wrote a script for a film version of Naked Lunch, which was never produced. The pair collaborated on a large manuscript for Grove Press titled The Third Mind, but it was determined that it would be impractical to publish it as originally envisioned. The book later published under that title incorporates little of this material. Interviewed for The Guardian in 1997, Burroughs explained that Gysin was "the only man that I've ever respected in my life. I've admired people, I've liked them, but he's the only man I've ever respected." In 1969, Gysin completed his finest novel, The Process, a work judged by critic Robert Palmer as "a classic of 20th century modernism".

A consummate innovator, Gysin altered the cut-up technique to produce what he called permutation poems in which a single phrase was repeated several times with the words rearranged in a different order with each reiteration. An example of this is "I don't dig work, man / Man, work I don't dig." Many of these permutations were derived using a random sequence generator in an early computer program written by Ian Sommerville. Commissioned by the BBC in 1960 to produce material for broadcast, Gysin's results included "Pistol Poem", which was created by recording a gun firing at different distances and then splicing the sounds. That year, the piece was subsequently used as a theme for the Paris performance of Le Domaine Poetique, a showcase for experimental works by people like Gysin, François Dufrêne, Bernard Heidsieck, and Henri Chopin.

With Sommerville, he built the Dreamachine in 1961. Described as "the first art object to be seen with the eyes closed", the flicker device uses alpha waves in the 8–16 Hz range to produce a change of consciousness in receptive viewers.

Later years
In April 1974, while sitting at a social engagement, Gysin had a very noticeable rectal bleeding. In May he wrote to Burroughs complaining he was not feeling well. A short time later he was diagnosed with colon cancer and began to receive cobalt treatment. Between December 1974 and April 1975, Gysin had to undergo several surgeries, among them a very traumatic colostomy, that drove him to extreme depression and to a suicide attempt. Later, in Fire: Words by Day – Images by Night (1975), a crudely lucid text, he would describe the horrendous ordeal he went through.

In 1985 Gysin was made an American Commander of the French Ordre des Arts et des Lettres. He'd begun to work extensively with noted jazz soprano saxophonist Steve Lacy. They recorded an album in 1986 with French musician Ramuntcho Matta, featuring Gysin singing/rapping his own texts, with performances by Lacy, Don Cherry, Elli Medeiros, Lizzy Mercier Descloux and more. The album was reissued on CD in 1993 by Crammed Discs, under the title Self-Portrait Jumping.

Death
On 13 July 1986 Brion Gysin died of lung cancer. Anne Cumming arranged his funeral and for his ashes to be scattered at the Caves of Hercules in Morocco. An obituary by Robert Palmer published in The New York Times described him as a man who "threw off the sort of ideas that ordinary artists would parlay into a lifetime career, great clumps of ideas, as casually as a locomotive throws off sparks". Later that year a heavily edited version of his novel, The Last Museum, was published posthumously by Faber & Faber (London) and by Grove Press (New York).

As a joke, Gysin had contributed a recipe for marijuana fudge to a cookbook by Alice B. Toklas; it was included for publication, becoming famous under the name Alice B. Toklas brownies.

Burroughs on the Gysin cut-up
In a 1966 interview by Conrad Knickerbocker for The Paris Review, William S. Burroughs explained that Brion Gysin was, to his knowledge, "the first to create cut-ups":

A friend, Brion Gysin, an American poet and painter, who has lived in Europe for thirty years, was, as far as I know, the first to create cut-ups. His cut-up poem, Minutes to Go, was broadcast by the BBC and later published in a pamphlet. I was in Paris in the summer of 1960; this was after the publication there of Naked Lunch. I became interested in the possibilities of this technique, and I began experimenting myself. Of course, when you think of it, The Waste Land was the first great cut-up collage, and Tristan Tzara had done a bit along the same lines. Dos Passos used the same idea in 'The Camera Eye' sequences in USA. I felt I had been working toward the same goal; thus it was a major revelation to me when I actually saw it being done.

Influence
According to José Férez Kuri, author of Brion Gysin: Tuning in to the Multimedia Age (2003) and co-curator of a major retrospective of the artist's work at The Edmonton Art Gallery in 1998, Gysin's wide range of "radical ideas would become a source of inspiration for artists of the Beat Generation, as well as for their successors (among them David Bowie, Mick Jagger, Keith Haring, and Laurie Anderson)". Other artists include Genesis P-Orridge, John Zorn (as displayed on the 2013's Dreamachines album) and Brian Jones.

Selected bibliography
Gysin is the subject of John Geiger's biography, Nothing Is True Everything Is Permitted: The Life of Brion Gysin, and features in Chapel of Extreme Experience: A Short History of Stroboscopic Light and the Dream Machine, also by Geiger. Man From Nowhere: Storming the Citadels of Enlightenment with William Burroughs and Brion Gysin, a biographical study of Burroughs and Gysin with a collection of homages to Gysin, was authored by Joe Ambrose, Frank Rynne, and Terry Wilson with contributions by Marianne Faithfull, John Cale, William S. Burroughs, John Giorno, Stanley Booth, Bill Laswell, Mohamed Hamri, Keith Haring and Paul Bowles. A monograph on Gysin was published in 2003 by Thames and Hudson.

Works
Prose
 * To Master, A Long Goodnight: The History of Slavery in Canada (1946)
 * Minutes to Go (1960)
 * The Exterminator (1960)
 * The Process (1969)
 * Brion Gysin Let The Mice In (1973)
 * The Third Mind (1978), with William S. Burroughs
 * Here To Go: Planet R-101 (first published 1982)
 * Stories (1984)
 * The Last Museum (1985)
 * Living with Islam (2010)
 * His Name Was Master (Interviews) (2018)

Radio
 * Pistol Poem (1960)
 * Permutations (1960)
 * I Am (1960)
 * No Poets (1962)
 * Junk is No Good Baby (1962)

Cinema Music Painting
 * Scenario to Naked Lunch (1973)
 * Songs (hat ART, 181) with Steve Lacy
 * Junk (1985)
 * Self-Portrait Jumping (with Ramuntcho Matta, Don Cherry, Steve Lacy) (1993)
 * Les deux faux interlocuteurs, Gradiva Rediviva Zoe Bertgang, and Signe dans le paysage (Surrealist ink drawings, 1935)
 * Sahara Sand (1958)
 * The Songs of Marrakech (1959)
 * Unit II pink, Unit III yellow, Unit IV orange, Unit V blue (1961)
 * Francis in the Beat Hotel (1962)
 * For a Stained-Glass Window in Rheims (1963)
 * Roller Poem (1971)
 * Calligraffiti of Fire (1986)

title: Brion Gysin


text:
Bulgarian

Bulgarian may refer to:

 * Something of, from, or related to the country of Bulgaria
 * Bulgarians, a South Slavic ethnic group
 * Bulgarian language, a Slavic language
 * Bulgarian alphabet
 * A citizen of Bulgaria, see Demographics of Bulgaria
 * Bulgarian culture
 * Bulgarian cuisine, a representative of the cuisine of Southeastern Europe

title: Bulgarian


text:
BCG vaccine

The Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB). It is named after its inventors Albert Calmette and Camille Guérin. In countries where tuberculosis or leprosy is common, one dose is recommended in healthy babies as soon after birth as possible. In areas where tuberculosis is not common, only children at high risk are typically immunized, while suspected cases of tuberculosis are individually tested for and treated. Adults who do not have tuberculosis and have not been previously immunized, but are frequently exposed, may be immunized, as well. BCG also has some effectiveness against Buruli ulcer infection and other nontuberculous mycobacterial infections. Additionally, it is sometimes used as part of the treatment of bladder cancer.

Rates of protection against tuberculosis infection vary widely and protection lasts up to 20 years. Among children, it prevents about 20% from getting infected and among those who do get infected, it protects half from developing disease. The vaccine is given by injection into the skin. No evidence shows that additional doses are beneficial.

Serious side effects are rare. Often, redness, swelling, and mild pain occur at the site of injection. A small ulcer may also form with some scarring after healing. Side effects are more common and potentially more severe in those with immunosuppression. Although no harmful effects on the fetus have been observed, there is insufficient evidence about the safety of BCG vaccination during pregnancy and therefore the vaccine is not recommended for use during pregnancy. The vaccine was originally developed from Mycobacterium bovis, which is commonly found in cattle. While it has been weakened, it is still live.

The BCG vaccine was first used medically in 1921. It is on the World Health Organization's List of Essential Medicines. , the vaccine is given to about 100 million children per year globally. However, it is not commonly administered in the United States.

Tuberculosis
The main use of BCG is for vaccination against tuberculosis. BCG vaccine can be administered after birth intradermally. BCG vaccination can cause a false positive Mantoux test.

The most controversial aspect of BCG is the variable efficacy found in different clinical trials, which appears to depend on geography. Trials conducted in the UK have consistently shown a protective effect of 60 to 80%, but those conducted elsewhere have shown no protective effect, and efficacy appears to fall the closer one gets to the equator.

A 1994 systematic review found that BCG reduces the risk of getting tuberculosis by about 50%. Differences in effectiveness depend on region, due to factors such as genetic differences in the populations, changes in environment, exposure to other bacterial infections, and conditions in the laboratory where the vaccine is grown, including genetic differences between the strains being cultured and the choice of growth medium.

A systematic review and meta-analysis conducted in 2014 demonstrated that the BCG vaccine reduced infections by 19–27% and reduced progression to active tuberculosis by 71%. The studies included in this review were limited to those that used interferon gamma release assay.

The duration of protection of BCG is not clearly known. In those studies showing a protective effect, the data are inconsistent. The MRC study showed protection waned to 59% after 15 years and to zero after 20 years; however, a study looking at Native Americans immunized in the 1930s found evidence of protection even 60 years after immunization, with only a slight waning in efficacy.

BCG seems to have its greatest effect in preventing miliary tuberculosis or tuberculosis meningitis, so it is still extensively used even in countries where efficacy against pulmonary tuberculosis is negligible.

The 100th anniversary of BCG was in 2021. It remains the only vaccine licensed against tuberculosis, which is an ongoing pandemic. Tuberculosis elimination is a goal of the World Health Organization (WHO), although the development of new vaccines with greater efficacy against adult pulmonary tuberculosis may be needed to make substantial progress.

Efficacy
A number of possible reasons for the variable efficacy of BCG in different countries have been proposed. None has been proven, some have been disproved, and none can explain the lack of efficacy in both low tuberculosis-burden countries (US) and high tuberculosis-burden countries (India). The reasons for variable efficacy have been discussed at length in a WHO document on BCG.
 * 1) Genetic variation in BCG strains: Genetic variation in the BCG strains used may explain the variable efficacy reported in different trials.
 * 2) Genetic variation in populations: Differences in genetic make-up of different populations may explain the difference in efficacy. The Birmingham BCG trial was published in 1988. The trial, based in Birmingham, United Kingdom, examined children born to families who originated from the Indian subcontinent (where vaccine efficacy had previously been shown to be zero). The trial showed a 64% protective effect, which is very similar to the figure derived from other UK trials, thus arguing against the genetic variation hypothesis.
 * 3) Interference by nontuberculous mycobacteria: Exposure to environmental mycobacteria (especially Mycobacterium avium, Mycobacterium marinum and Mycobacterium intracellulare) results in a nonspecific immune response against mycobacteria. Administering BCG to someone who already has a nonspecific immune response against mycobacteria does not augment the response already there. BCG will, therefore, appear not to be efficacious because that person already has a level of immunity and BCG is not adding to that immunity. This effect is called masking because the effect of BCG is masked by environmental mycobacteria. Clinical evidence for this effect was found in a series of studies performed in parallel in adolescent school children in the UK and Malawi. In this study, the UK school children had a low baseline cellular immunity to mycobacteria which was increased by BCG; in contrast, the Malawi school children had a high baseline cellular immunity to mycobacteria and this was not significantly increased by BCG. Whether this natural immune response is protective is not known. An alternative explanation is suggested by mouse studies; immunity against mycobacteria stops BCG from replicating and so stops it from producing an immune response. This is called the block hypothesis.
 * 4) Interference by concurrent parasitic infection: In another hypothesis, simultaneous infection with parasites such as helminthiasis changes the immune response to BCG, making it less effective. As Th1 response is required for an effective immune response to tuberculous infection, concurrent infection with various parasites produces a simultaneous Th2 response, which blunts the effect of BCG.

Mycobacteria
BCG has protective effects against some nontuberculosis mycobacteria.
 * Leprosy: BCG has a protective effect against leprosy in the range of 20 to 80%.
 * Buruli ulcer: BCG may protect against or delay the onset of Buruli ulcer.

Cancer

BCG has been one of the most successful immunotherapies. BCG vaccine has been the "standard of care for patients with bladder cancer (NMIBC)" since 1977. By 2014 there were more than eight different considered biosimilar agents or strains used for the treatment of nonmuscle-invasive bladder cancer.
 * A number of cancer vaccines use BCG as an additive to provide an initial stimulation of the person's immune systems.
 * BCG is used in the treatment of superficial forms of bladder cancer. Since the late 1970s, evidence has become available that instillation of BCG into the bladder is an effective form of immunotherapy in this disease. While the mechanism is unclear, it appears a local immune reaction is mounted against the tumor. Immunotherapy with BCG prevents recurrence in up to 67% of cases of superficial bladder cancer.
 * BCG has been evaluated in a number of studies as a therapy for colorectal cancer. The US biotech company Vaccinogen is evaluating BCG as an adjuvant to autologous tumour cells used as a cancer vaccine in stage II colon cancer.

Method of administration

A pre-injection tuberculin skin test is usually carried out before administering BCG. A reactive tuberculin skin test is a contraindication to BCG due to the risk of severe local inflammation and scarring; it does not indicate any immunity. BCG is also contraindicated in certain people who have IL-12 receptor pathway defects.

BCG is given as a single intradermal injection at the insertion of the deltoid. If BCG is accidentally given subcutaneously, then a local abscess may form (a "BCG-oma") that can sometimes ulcerate, and may require treatment with antibiotics immediately, otherwise without treatment it could spread the infection, causing severe damage to vital organs. An abscess is not always associated with incorrect administration, and it is one of the more common complications that can occur with the vaccination. Numerous medical studies on treatment of these abscesses with antibiotics have been done with varying results, but the consensus is once pus is aspirated and analysed, provided no unusual bacilli are present, the abscess will generally heal on its own in a matter of weeks.

The characteristic raised scar that BCG immunization leaves is often used as proof of prior immunization. This scar must be distinguished from that of smallpox vaccination, which it may resemble.

When given for bladder cancer, the vaccine is not injected through the skin, but is instilled into the bladder through the urethra using a soft catheter.

Adverse effects
BCG immunization generally causes some pain and scarring at the site of injection. The main adverse effects are keloids—large, raised scars. The insertion to the deltoid muscle is most frequently used because the local complication rate is smallest when that site is used. Nonetheless, the buttock is an alternative site of administration because it provides better cosmetic outcomes.

BCG vaccine should be given intradermally. If given subcutaneously, it may induce local infection and spread to the regional lymph nodes, causing either suppurative (production of pus) and nonsuppurative lymphadenitis. Conservative management is usually adequate for nonsuppurative lymphadenitis. If suppuration occurs, it may need needle aspiration. For nonresolving suppuration, surgical excision may be required. Evidence for the treatment of these complications is scarce.

Uncommonly, breast and gluteal abscesses can occur due to haematogenous (carried by the blood) and lymphangiomatous spread. Regional bone infection (BCG osteomyelitis or osteitis) and disseminated BCG infection are rare complications of BCG vaccination, but potentially life-threatening. Systemic antituberculous therapy may be helpful in severe complications.

When BCG is used for bladder cancer, around 2.9% of treated patients discontinue immunotherapy due to a genitourinary or systemic BCG-related infection, however while symptomatic bladder BCG infection is frequent, the involvement of other organs is very uncommon. When systemic involvement occurs, liver and lungs are the first organs to be affected (1 week [median] after the last BCG instillation).

If BCG is accidentally given to an immunocompromised patient (e.g., an infant with severe combined immune deficiency), it can cause disseminated or life-threatening infection. The documented incidence of this happening is less than one per million immunizations given. In 2007, the WHO stopped recommending BCG for infants with HIV, even if the risk of exposure to tuberculosis is high, because of the risk of disseminated BCG infection (which is roughly 400 per 100,000 in that higher risk context).

Usage
The age of the person and the frequency with which BCG is given has always varied from country to country. The WHO currently recommends childhood BCG for all countries with a high incidence of tuberculosis and/or high leprosy burden. This is a partial list of historic and current BCG practice around the globe. A complete atlas of past and present practice has been generated.

Americas

 * Brazil introduced universal BCG immunization in 1967–1968, and the practice continues until now. According to Brazilian law, BCG is given again to professionals of the health sector and to people close to patients with tuberculosis or leprosy.
 * Canadian Indigenous communities currently receive the BCG vaccine, and in the province of Quebec the vaccine was offered to children until the mid-70s.
 * Most countries in Central and South America have universal BCG immunizations, as does Mexico.
 * The United States has never used mass immunization of BCG due to the rarity of tuberculosis in the US, relying instead on the detection and treatment of latent tuberculosis.

Asia

 * China: Introduced in 1930s. Increasingly widespread after 1949. Majority inoculated by 1979.
 * South Korea, Singapore, Taiwan and Malaysia. In these countries, BCG was given at birth and again at age 12. In Malaysia and Singapore from 2001, this policy was changed to once only at birth. South Korea stopped re-vaccination in 2008.
 * Hong Kong: BCG is given to all newborns.
 * Japan: In Japan, BCG was introduced in 1951, given typically at age 6. From 2005 it is administered between five and eight months after birth, and no later than a child's first birthday. BCG was administered no later than the fourth birthday until 2005, and no later than six months from birth from 2005 to 2012; the schedule was changed in 2012 due to reports of osteitis side effects from vaccinations at 3–4 months. Some municipalities recommend an earlier immunization schedule.
 * Thailand: In Thailand, the BCG vaccine is given routinely at birth.
 * India and Pakistan: India and Pakistan introduced BCG mass immunization in 1948, the first countries outside Europe to do so. In 2015, millions of infants were denied BCG vaccine in Pakistan for the first time due to shortage globally.
 * Mongolia: All newborns are vaccinated with BCG. Previously, the vaccine was also given at ages 8 and 15, although this is no longer common practice.
 * Philippines: BCG vaccine started in the Philippines in 1979 with the Expanded Program on Immunization.
 * Sri Lanka: In Sri Lanka, The National Policy of Sri Lanka is to give BCG vaccination to all newborn babies immediately after birth. BCG vaccination is carried out under the Expanded Programme of Immunisation (EPI).

Middle East

 * Israel: BCG was given to all newborns between 1955 and 1982.
 * Iran: Iran's vaccination policy implemented in 1984. Vaccination with the Bacillus Calmette–Guerin (BCG) is among the most important tuberculosis control strategies in Iran [2]. According to Iranian neonatal vaccination policy, BCG has been given as a single dose at children aged <6 years, shortly after birth or at first contact with the health services.

Africa

 * South Africa: In South Africa, the BCG Vaccine is given routinely at birth, to all newborns, except those with clinically symptomatic AIDS. The vaccination site is in the right shoulder.
 * Morocco: In Morocco, the BCG was introduced in 1949. The current policy is BCG vaccination at birth, to all newborns.
 * Kenya: In Kenya, the BCG Vaccine is given routinely at birth to all newborns.

South Pacific

 * Australia: BCG vaccination was used between 1950s and mid 1980. BCG is not part of routine vaccination since mid 1980.
 * New Zealand: BCG Immunisation was first introduced for 13 yr olds in 1948. Vaccination was phased out 1963–1990.

Manufacture
BCG is prepared from a strain of the attenuated (virulence-reduced) live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its ability to cause disease in humans. It is specially subcultured in a culture medium, usually Middlebrook 7H9. Because the living bacilli evolve to make the best use of available nutrients, they become less well-adapted to human blood and can no longer induce disease when introduced into a human host. Still, they are similar enough to their wild ancestors to provide some degree of immunity against human tuberculosis. The BCG vaccine can be anywhere from 0 to 80% effective in preventing tuberculosis for a duration of 15 years; however, its protective effect appears to vary according to geography and the lab in which the vaccine strain was grown.

A number of different companies make BCG, sometimes using different genetic strains of the bacterium. This may result in different product characteristics. OncoTICE, used for bladder instillation for bladder cancer, was developed by Organon Laboratories (since acquired by Schering-Plough, and in turn acquired by Merck & Co.). A similar application is the product of Onko BCG of the Polish company Biomed-Lublin, which owns the Brazilian substrain M. bovis BCG Moreau which is less reactogenic than vaccines including other BCG strains. Pacis BCG, made from the Montréal (Institut Armand-Frappier) strain, was first marketed by Urocor in about 2002. Urocor was since acquired by Dianon Systems. Evans Vaccines (a subsidiary of PowderJect Pharmaceuticals). Statens Serum Institut in Denmark has marketed BCG vaccine prepared using Danish strain 1331. The production of BCG Danish strain 1331 and its distribution was later undertaken by AJVaccines company since the ownership transfer of SSI's vaccine production business to AJ Vaccines Holding A/S which took place on 16 January 2017. Japan BCG Laboratory markets its vaccine, based on the Tokyo 172 substrain of Pasteur BCG, in 50 countries worldwide.

According to a UNICEF report published in December 2015, on BCG vaccine supply security, global demand increased in 2015 from 123 to 152.2 million doses. To improve security and to [diversify] sources of affordable and flexible supply," UNICEF awarded seven new manufacturers contracts to produce BCG. Along with supply availability from existing manufacturers, and a "new WHO prequalified vaccine" the total supply will be "sufficient to meet both suppressed 2015 demand carried over to 2016, as well as total forecast demand through 2016–2018."

Supply shortage
In 2011, the Sanofi Pasteur plant flooded, causing problems with mold. The facility, located in Toronto, Ontario, Canada, produced BCG vaccine products made with substrain Connaught such as a tuberculosis vaccine and ImmuCYST, a BCG immunotherapeutic and bladder cancer drug. By April 2012 the FDA had found dozens of documented problems with sterility at the plant including mold, nesting birds and rusted electrical conduits. The resulting closure of the plant for over two years caused shortages of bladder cancer and tuberculosis vaccines. On 29 October 2014 Health Canada gave the permission for Sanofi to resume production of BCG. A 2018 analysis of the global supply concluded that the supplies are adequate to meet forecast BCG vaccine demand, but that risks of shortages remain, mainly due to dependence of 75 percent of WHO pre-qualified supply on just two suppliers.

Dried
Some BCG vaccines are freeze dried and become fine powder. Sometimes the powder is sealed with vacuum in a glass ampoule. Such a glass ampoule has to be opened slowly to prevent the airflow from blowing out the powder. Then the powder has to be diluted with saline water before injecting.

History
The history of BCG is tied to that of smallpox. By 1865 Jean Antoine Villemin had demonstrated that rabbits could be infected with tuberculosis from humans; by 1868 he had found that rabbits could be infected with tuberculosis from cows, and that rabbits could be infected with tuberculosis from other rabbits. Thus, he concluded that tuberculosis was transmitted via some unidentified microorganism (or "virus", as he called it). In 1882 Robert Koch regarded human and bovine tuberculosis as identical. But in 1895, Theobald Smith presented differences between human and bovine tuberculosis, which he reported to Koch. By 1901 Koch distinguished Mycobacterium bovis from Mycobacterium tuberculosis. Following the success of vaccination in preventing smallpox, established during the 18th century, scientists thought to find a corollary in tuberculosis by drawing a parallel between bovine tuberculosis and cowpox: it was hypothesized that infection with bovine tuberculosis might protect against infection with human tuberculosis. In the late 19th century, clinical trials using M. bovis were conducted in Italy with disastrous results, because M. bovis was found to be just as virulent as M. tuberculosis.

Albert Calmette, a French physician and bacteriologist, and his assistant and later colleague, Camille Guérin, a veterinarian, were working at the Institut Pasteur de Lille (Lille, France) in 1908. Their work included subculturing virulent strains of the tuberculosis bacillus and testing different culture media. They noted a glycerin-bile-potato mixture grew bacilli that seemed less virulent, and changed the course of their research to see if repeated subculturing would produce a strain that was attenuated enough to be considered for use as a vaccine. The BCG strain was isolated after subculturing 239 times during 13 years from virulent strain on glycerine potato medium. The research continued throughout World War I until 1919, when the now avirulent bacilli were unable to cause tuberculosis disease in research animals. Calmette and Guerin transferred to the Paris Pasteur Institute in 1919. The BCG vaccine was first used in humans in 1921.

Public acceptance was slow, and the Lübeck disaster, in particular, did much to harm it. Between 1929 and 1933 in Lübeck, 251 infants were vaccinated in the first 10 days of life; 173 developed tuberculosis and 72 died. It was subsequently discovered that the BCG administered there had been contaminated with a virulent strain that was being stored in the same incubator, which led to legal action against the manufacturers of the vaccine.

Dr. R. G. Ferguson, working at the Fort Qu'Appelle Sanatorium in Saskatchewan, was among the pioneers in developing the practice of vaccination against tuberculosis. In Canada, more than 600 children from residential schools were used as involuntary participants in BCG vaccine trials between 1933 and 1945. In 1928, BCG was adopted by the Health Committee of the League of Nations (predecessor to the World Health Organization (WHO)). Because of opposition, however, it only became widely used after World War II. From 1945 to 1948, relief organizations (International Tuberculosis Campaign or Joint Enterprises) vaccinated over eight million babies in eastern Europe and prevented the predicted typical increase of tuberculosis after a major war.

BCG is very efficacious against tuberculous meningitis in the pediatric age group, but its efficacy against pulmonary tuberculosis appears to be variable. Some countries have removed BCG from routine vaccination. Two countries that have never used it routinely are the United States and the Netherlands (in both countries, it is felt that having a reliable Mantoux test and therefore being able to accurately detect active disease is more beneficial to society than vaccinating against a condition that is now relatively rare there).

Other names include "Vaccin Bilié de Calmette et Guérin vaccine" and "Bacille de Calmette et Guérin vaccine".

Research
Tentative evidence exists for a beneficial non-specific effect of BCG vaccination on overall mortality in low income countries, or for its reducing other health problems including sepsis and respiratory infections when given early, with greater benefit the earlier it is used.

In rhesus macaques, BCG shows improved rates of protection when given intravenously. Some risks must be evaluated before it can be translated to humans.

The University of Oxford Jenner Institute is conducting a study comparing the efficacy of injected versus inhaled BCG vaccine in already-vaccinated adults.

Type 1 diabetes
, BCG vaccine is in the early stages of being studied in type 1 diabetes (T1D).

COVID-19
Use of the BCG vaccine may provide protection against COVID-19. However, epidemiologic observations in this respect are ambiguous. The WHO does not recommend its use for prevention.

, twenty BCG trials are in various clinical stages. , the results are extremely mixed. A 15-month trial involving people thrice-vaccinated over the two years before the pandemic shows positive results in preventing infection in BCG-naive people with type 1 diabetes. On the other hand, a 5-month trial shows that re-vaccinating with BCG does not help prevent infection in healthcare workers. Both of these trials were double-blind randomized controlled trials.

title: BCG vaccine


text:
Bunsen

Bunsen may refer to:
 * Christian Charles Josias Bunsen (1791–1860), Prussian diplomat and scholar
 * Frances Bunsen (1791–1876), or Baroness Bunsen, Welsh painter and author, wife of Christian Charles Josias Bunsen
 * Robert Bunsen (1811–1899), German chemist, after whom is named:
 * Bunsen burner
 * Bunsen cell
 * Bunsen crater on the Moon
 * 10361 Bunsen, an asteroid
 * Bunsen Reaction
 * The Bunsen–Kirchhoff Award, a German award for spectroscopy
 * Sir Maurice de Bunsen (1852–1932), British diplomat
 * Dr. Bunsen Honeydew, fictional character from the Muppet Show

title: Bunsen