In most contexts, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to cause disease—is determined by its virulence factors. In the specific context of gene for gene systems, often in plants, virulence refers to a pathogen's ability to infect a resistant host.
The nounvirulence derives from the adjectivevirulent, meaning disease severity. The word virulent derives from the Latin word virulentus, meaning "a poisoned wound" or "full of poison."
From an ecological standpoint, virulence is the loss of fitness induced by a parasite upon its host. Virulence can be understood in terms of proximate causes—those specific traits of the pathogen that help make the host ill—and ultimate causes—the evolutionary pressures that lead to virulent traits occurring in a pathogen strain.
Virulent bacteria
The ability of bacteria
to cause disease is described in terms of the number of infecting
bacteria, the route of entry into the body, the effects of host defense
mechanisms, and intrinsic characteristics of the bacteria called virulence factors. Many virulence factors are so-called effector proteins that are injected into the host cells by specialized secretion apparati, such as the type three secretion system.
Host-mediated pathogenesis is often important because the host can
respond aggressively to infection with the result that host defense
mechanisms do damage to host tissues while the infection is being
countered (e.g., cytokine storm).
The virulence factors of bacteria are typically proteins or other molecules that are synthesized by enzymes. These proteins are coded for by genes in chromosomal DNA, bacteriophage DNA or plasmids. Certain bacteria employ mobile genetic elements and horizontal gene transfer.
Therefore, strategies to combat certain bacterial infections by
targeting these specific virulence factors and mobile genetic elements
have been proposed. Bacteria use quorum sensing to synchronise release of the molecules. These are all proximate causes of morbidity in the host.
Methods by which bacteria cause disease
Invasion
Adhesion. Many bacteria must first bind to host cell surfaces.
Many bacterial and host molecules that are involved in the adhesion of
bacteria to host cells have been identified. Often, the host cell surface receptors for bacteria are essential proteins for other functions. Due to the presence of mucus
lining and of anti-microbial substances around some host cells, it is
difficult for certain pathogens to establish direct contact-adhesion.
Colonization. Some virulent bacteria produce special proteins that allow them to colonize parts of the host body. Helicobacter pylori is able to survive in the acidic environment of the human stomach by producing the enzyme urease. Colonization of the stomach lining by this bacterium can lead to gastric ulcers and cancer. The virulence of various strains of Helicobacter pylori tends to correlate with the level of production of urease.
Invasion. Some virulent bacteria produce proteins that either disrupt host cell membranes or stimulate their own endocytosis or macropinocytosis
into host cells. These virulence factors allow the bacteria to enter
host cells and facilitate entry into the body across epithelial tissue
layers at the body surface.
Immune response inhibitors. Many bacteria produce virulence factors
that inhibit the host's immune system defenses. For example, a common
bacterial strategy is to produce proteins that bind host antibodies. The
polysaccharidecapsule of Streptococcus pneumoniae inhibits phagocytosis of the bacterium by host immune cells.
Toxins. Many virulence factors are proteins made by bacteria that
poison host cells and cause tissue damage. For example, there are many food poisoningtoxins
produced by bacteria that can contaminate human foods. Some of these
can remain in "spoiled" food even after cooking and cause illness when
the contaminated food is consumed. Other bacterial toxins are chemically
altered and inactivated by the heat of cooking.
Virulent viruses
Virus virulence factors allow it to replicate, modify host defenses, and spread within the host, and they are toxic to the host.
They determine whether infection occurs and how severe the
resulting viral disease symptoms are. Viruses often require receptor
proteins on host cells to which they specifically bind. Typically, these
host cell proteins are endocytosed and the bound virus then enters the host cell. Virulent viruses such as HIV, which causes AIDS, have mechanisms for evading host defenses. HIV infects T-helper cells,
which leads to a reduction of the adaptive immune response of the host
and eventually leads to an immunocompromised state. Death results from
opportunistic infections secondary to disruption of the immune system
caused by AIDS. Some viral virulence factors confer ability to replicate
during the defensive inflammation responses of the host such as during
virus-induced fever.
Many viruses can exist inside a host for long periods during which
little damage is done. Extremely virulent strains can eventually evolve by mutation and natural selection within the virus population inside a host. The term "neurovirulent" is used for viruses such as rabies and herpes simplex which can invade the nervous system and cause disease there.
Every year, thousands of cases of the plague are still reported to the World Health Organization, although with proper antibiotic treatment, the prognosis for victims is now much better. A five- to six-fold increase in cases occurred in Asia during the time of the Vietnam War,
possibly due to the disruption of ecosystems and closer proximity
between people and animals. The plague is now commonly found in
sub-Saharan Africa and Madagascar, areas that now account for over 95%
of reported cases. The plague also has a detrimental effect on nonhuman
mammals; in the United States, these include the black-tailed prairie dog and the endangered black-footed ferret.
General characteristics
Y. pestis is a nonmotile, stick-shaped, facultative anaerobic bacterium with bipolar staining (giving it a safety pin appearance) that produces an antiphagocytic slime layer. Similar to other Yersinia species, it tests negative for urease, lactose fermentation, and indole. Its closest relative is the gastrointestinal pathogen Yersinia pseudotuberculosis, and more distantly Yersinia enterocolitica.
Genome
A complete genomic sequence is available for two of the three subspecies of Y. pestis: strain KIM (of biovar Y. p. medievalis), and strain CO92 (of biovar Y. p. orientalis, obtained from a clinical isolate in the United States). As of 2006, the genomic sequence of a strain of biovar Antiqua has been recently completed. Similar to the other pathogenic strains, signs exist of loss of function mutations. The chromosome of strain KIM is 4,600,755 base pairs long; the chromosome of strain CO92 is 4,653,728 base pairs long. Like Y. pseudotuberculosis and Y. enterocolitica, Y. pestis is host to the plasmid
pCD1. It also hosts two other plasmids, pPCP1 (also called pPla or
pPst) and pMT1 (also called pFra) that are not carried by the other Yersinia species. pFra codes for a phospholipase D that is important for the ability of Y. pestis to be transmitted by fleas. pPla codes for a protease, Pla, that activates plasmin in human hosts and is a very important virulence factor for pneumonic plague. Together, these plasmids, and a pathogenicity island called HPI, encode several proteins that cause the pathogenesis, for which Y. pestis
is famous. Among other things, these virulence factors are required for
bacterial adhesion and injection of proteins into the host cell,
invasion of bacteria in the host cell (via a type-III secretion system), and acquisition and binding of iron harvested from red blood cells (by siderophores). Y. pestis is thought to be descended from Y. pseudotuberculosis, differing only in the presence of specific virulence plasmids.
A comprehensive and comparative proteomics analysis of Y. pestis strain KIM was performed in 2006. The analysis focused on the transition to a growth condition mimicking growth in host cells.
Small noncoding RNA
Numerous bacterial small noncoding RNAs
have been identified to play regulatory functions. Some can regulate
the virulence genes. Some 63 novel putative sRNAs were identified
through deep sequencing of the Y. pestis sRNA-ome. Among them was Yersinia-specific (also present in Y. pseudotuberculosis and Y. enterocolitica) Ysr141 (Yersinia small RNA 141). Ysr141 sRNA was shown to regulate the synthesis of the type III secretion system (T3SS) effector protein YopJ. The Yop-Ysc T3SS is a critical component of virulence for Yersinia species. Many novel sRNAs were identified from Y. pestis grown in vitro and in the infected lungs of mice suggesting they play role in bacterial physiology or pathogenesis. Among them sR035 predicted to pair with SD region and transcription initiation site of a thermo-sensitive regulator ymoA, and sR084 predicted to pair with fur, ferric uptake regulator.
Pathogenesis and immunity
Oriental rat flea (Xenopsylla cheopis) infected with the Y. pestisbacterium, which appears as a dark mass in the gut: The foregut (proventriculus) of this flea is blocked by a Y. pestisbiofilm; when the flea attempts to feed on an uninfected host, Y. pestis is regurgitated into the wound, causing infection.
In the urban and sylvatic (forest) cycles of Y. pestis, most of the spreading occurs between rodents and fleas. In the sylvatic cycle, the rodent is wild, but in the urban cycle, the rodent is primarily the brown rat (Rattus norvegicus). In addition, Y. pestis
can spread from the urban environment and back. Transmission to humans
is usually through the bite of infected fleas. If the disease has
progressed to the pneumonic form, humans can spread the bacterium to
others by coughing, vomiting, and possibly sneezing.
In reservoir hosts
Several species of rodents serve as the main reservoir for Y. pestis in the environment. In the steppes, the natural reservoir is believed to be principally the marmot. In the western United States, several species of rodents are thought to maintain Y. pestis.
However, the expected disease dynamics have not been found in any
rodent. Several species of rodents are known to have a variable
resistance, which could lead to an asymptomatic carrier status. Evidence indicates fleas from other mammals have a role in human plague outbreaks.
The lack of knowledge of the dynamics of plague in mammal species
is also true among susceptible rodents such as the black-tailed prairie
dog (Cynomys ludovicianus), in which plague can cause colony collapse, resulting in a massive effect on prairie food webs.
However, the transmission dynamics within prairie dogs do not follow
the dynamics of blocked fleas; carcasses, unblocked fleas, or another
vector could possibly be important, instead.
In other regions of the world, the reservoir of the infection is
not clearly identified, which complicates prevention and early-warning
programs. One such example was seen in a 2003 outbreak in Algeria.
Vector
The transmission of Y. pestis by fleas is well characterized. Initial acquisition of Y. pestis by the vector
occurs during feeding on an infected animal. Several proteins then
contribute to the maintenance of the bacteria in the flea digestive
tract, among them the hemin storage system and Yersiniamurine
toxin (Ymt).
Although Ymt is highly toxic to rodents and was once thought to be
produced to ensure reinfection of new hosts, it is important for the
survival of Y. pestis in fleas.
The hemin storage system plays an important role in the transmission of Y. pestis back to a mammalian host. While in the insect vector, proteins encoded by hemin storage system genetic loci induce biofilm formation in the proventriculus, a valve connecting the midgut to the esophagus. The presence of this biofilm seems likely to be required for stable infection of the flea.
Aggregation in the biofilm inhibits feeding, as a mass of clotted blood
and bacteria forms (referred to as "Bacot's block" after entomologist A.W. Bacot, the first to describe this phenomenon). Transmission of Y. pestis
occurs during the futile attempts of the flea to feed. Ingested blood
is pumped into the esophagus, where it dislodges bacteria lodged in the
proventriculus, which is regurgitated back into the host circulatory
system.
In humans and other susceptible hosts
Pathogenesis due to Y. pestis infection of mammalian hosts is due to several factors, including an ability of these bacteria to suppress and avoid normal immune system responses such as phagocytosis and antibody production. Flea bites allow for the bacteria to pass the skin barrier. Y. pestis expresses a plasmin
activator that is an important virulence factor for pneumonic plague
and that might degrade on blood clots to facilitate systematic invasion. Many of the bacteria's virulence factors are antiphagocytic in nature. Two important antiphagocytic antigens, named F1 (fraction 1) and V or LcrV, are both important for virulence. These antigens are produced by the bacterium at normal human body temperature. Furthermore, Y. pestis survives and produces F1 and V antigens while it is residing within white blood cells such as monocytes, but not in neutrophils. Natural or induced immunity is achieved by the production of specific opsonic antibodies against F1 and V antigens; antibodies against F1 and V induce phagocytosis by neutrophils.
In addition, the type-III secretion system (T3SS) allows Y. pestis to inject proteins into macrophages and other immune cells. These T3SS-injected proteins, called Yersinia outer proteins (Yops), include Yop B/D, which form pores in the host cell membrane and have been linked to cytolysis. The YopO, YopH, YopM, YopT, YopJ, and YopE are injected into the cytoplasm of host cells by T3SS into the pore created in part by YopB and YopD. The injected Yops limit phagocytosis and cell signaling pathways important in the innate immune system, as discussed below. In addition, some Y. pestis strains are capable of interfering with immune signaling (e.g., by preventing the release of some cytokines).
YopE functions as a GTPase-activating protein for members of the Rho family of GTPases such as RAC1. YopT is a cysteine protease that inhibits RhoA by removing the isoprenyl group, which is important for localizing the protein to the cell membrane. YopE and YopT has been proposed to function to limit YopB/D-induced cytolysis.
This might limit the function of YopB/D to create the pores used for
Yop insertion into host cells and prevent YopB/D-induced rupture of host
cells and release of cell contents that would attract and stimulate
immune system responses.
YopJ is an acetyltransferase that binds to a conserved α-helix of MAPK kinases. YopJ acetylates MAPK kinases at serines and threonines that are normally phosphorylated during activation of the MAP kinase cascade. YopJ is activated in eukaryotic cells by interaction with target cell phytic acid (IP6). This disruption of host cell protein kinase activity causes apoptosis
of macrophages, and this is proposed to be important for the
establishment of infection and for evasion of the host immune response.
YopO is a protein kinase also known as Yersinia protein kinase A (YpkA). YopO is a potent inducer of human macrophage apoptosis.
It has also been suggested that a bacteriophage – Ypφ – may have been responsible for increasing the virulence of this organism.
Depending on which form of the plague with which the individual
becomes infected, the plague develops a different illness; however, the
plague overall affects the host cell's ability to communicate with the
immune system, hindering the body to bring phagocytic cells to the area
of infection.
Y. pestis is a versatile killer. In addition to rodents and humans, it is known to have killed camels, chickens, and pigs.
Domestic dogs and cats are susceptible to plague, as well, but cats are
more likely to develop illness when infected. In either, the symptoms
are similar to those experienced by humans, and can be deadly to the
animal. People can be exposed by coming into contact with an infected
animal (dead or alive), or inhaling infectious droplets that a sick dog
or cat has coughed into the air.
Immunity
A formalin-inactivated vaccine was in the past available in the United States for adults at high risk of contracting the plague until removal from the market by the Food and Drug Administration. It was of limited effectiveness and could cause severe inflammation. Experiments with genetic engineering
of a vaccine based on F1 and V antigens are underway and show promise.
However, bacteria lacking antigen F1 are still virulent, and the V
antigens are sufficiently variable such that vaccines composed of these
antigens may not be fully protective. The United States Army Medical Research Institute of Infectious Diseases has found that an experimental F1/V antigen-based vaccine protects crab-eating macaques, but fails to protect African green monkey species. A systematic review by the Cochrane Collaboration found no studies of sufficient quality to make any statement on the efficacy of the vaccine.
In 1894, two bacteriologists, Alexandre Yersin of Switzerland and Kitasato Shibasaburō of Japan, independently isolated in Hong Kong the bacterium responsible for the 1894 Hong Kong plague.
Though both investigators reported their findings, a series of
confusing and contradictory statements by Kitasato eventually led to the
acceptance of Yersin as the primary discoverer of the organism. Yersin
named it Pasteurella pestis in honor of the Pasteur Institute, where he worked. In 1967, it was moved to a new genus and renamed Yersinia pestis
in his honor. Yersin also noted that rats were affected by plague not
only during plague epidemics, but also often preceding such epidemics in
humans and that plague was regarded by many locals as a disease of
rats; villagers in China and India asserted that when large numbers of
rats were found dead, plague outbreaks soon followed.
In 1898, French scientist Paul-Louis Simond (who had also come to China to battle the Third Pandemic) discovered the rat–flea vector
that drives the disease. He had noted that persons who became ill did
not have to be in close contact with each other to acquire the disease.
In Yunnan, China, inhabitants would flee from their homes as soon as they saw dead rats, and on the island of Formosa (Taiwan),
residents considered the handling of dead rats heightened the risks of
developing plague. These observations led him to suspect that the flea
might be an intermediary factor in the transmission of plague, since
people acquired plague only if they were in contact with rats that had
died less than 24 hours before. In a now classic experiment, Simond
demonstrated how a healthy rat died of the plague after infected fleas
had jumped to it from a rat that had recently died of the plague. The outbreak spread to Chinatown, San Francisco, from 1900 to 1904 and then to Oakland and the East Bay from 1907 to 1909.
It has been present in the rodents of western North America ever since,
as fear of the consequences of the outbreak on trade caused authorities
to hide the dead of the Chinatown residents long enough for the disease
to be passed to widespread species of native rodents in outlying areas.
Ancient DNA evidence
In 2018, the emergence and spread of the pathogen during the Neolithic decline (as far back as 6,000 years ago) was published.
A site in Sweden was the source of the DNA evidence and trade networks
were proposed as the likely avenue of spread rather than migrations of
populations.
DNA evidence published in 2015 indicates Y. pestis infected humans 5,000 years ago in Bronze Age Eurasia, but genetic changes that made it highly virulent did not occur until about 4,000 years ago.
The highly virulent version capable of transmission by fleas through
rodents, humans, and other mammals was found in two individuals
associated with the Srubnaya culture from the Samara region in Russia from around 3,800 years ago and an Iron Age individual from Kapan, Armenia from around 2,900 years ago. This indicates that at least two lineages of Y. pestis were circulating during the Bronze Age in Eurasia. The Y. pestis
bacterium has a relatively large number of nonfunctioning genes and
three "ungainly" plasmids, suggesting an origin less than 20,000 years
ago.
Three main strains are recognised: Y. p. antiqua, which caused a plague pandemic in the sixth century; Y. p. medievalis, which caused the Black Death and subsequent epidemics during the second pandemic wave; and Y. p. orientalis, which is responsible for current plague outbreaks.
Recent events
In
2008, the plague was commonly found in sub-Saharan Africa and
Madagascar, areas that accounted for over 95% of the reported cases.
In September 2009, the death of Malcolm Casadaban, a molecular genetics professor at the University of Chicago, was linked to his work on a weakened laboratory strain of Y. pestis. Hemochromatosis was hypothesised to be a predisposing factor in Casadaban's death from this attenuated strain used for research.
In 2010, researchers in Germany definitely established, using PCR evidence from samples obtained from Black Death victims, that Y. pestis was the cause of the medieval Black Death.
In 2011, the first genome of Y. pestis isolated from Black Death victims was published, and concluded that this medieval strain was ancestral to most modern forms of Y. pestis.
On September 8, 2016, the Y. pestis bacterium was identified from DNA in teeth found at a Crossrail building site in London. The human remains were found to be victims of the Great Plague of London, which lasted from 1665 to 1666.
On January 15, 2018, researchers at the University of Oslo and the University of Ferrara suggested that humans and their parasites were the biggest carriers of the plague.
On November 3, 2019, two cases of pneumonic plague were diagnosed at a hospital in Beijing's Chaoyang
district, prompting fears of an outbreak. Doctors diagnosed a
middle-aged man with fever, who had complained of difficulty breathing
for some ten days, accompanied by his wife with similar symptoms. Police quarantined the emergency room at the hospital and controls were placed on Chinese news aggregators. On the 18th, a third case was reported in a 55-year-old male from Xilingol League, one of the twelve Mongolic autonomous regions in Northern China. The patient received treatment and 28 symptomless contacts were placed in quarantine.
In July 2020, officials increased precautions after a case of bubonic plague was confirmed in Bayannur, a city in China's Inner Mongolia autonomous region. The patient was quarantined and treated. According to China's Global Times,
a second suspected case was also investigated, and a level 3 alert was
issued, in effect until the end of the year. It forbade hunting and
eating of animals that could carry plague and called on the public to
report suspected cases.
Common side effects include diarrhea, nausea, vomiting, and an increased risk of sunburn. Use after the first trimester of pregnancy or in young children may result in permanent discoloration of the teeth. Its use during breastfeeding is probably safe. Doxycycline is a broad-spectrum antibiotic, of the tetracycline class. Use of any antibiotic has been shown to increase a person's risk of multiple sclerosis, with a relative risk that depends on the class of antibiotic; tetracyclines increase a person's risk of MS by an average of 33%. Like other agents of the tetracycline class, it either slows or kills bacteria by inhibiting protein production. It kills malaria by targeting a plastid organelle, the apicoplast.
Doxycycline was patented in 1957 and came into commercial use in 1967. It is on the World Health Organization's List of Essential Medicines. Doxycycline is available as a generic medicine. In 2018, it was the 80th most commonly prescribed medication in the United States, with more than 10million prescriptions. It is available in India under the brand name DOXY-1- LDR.
Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsia
Respiratory tract infections caused by Mycoplasma pneumoniae
Lymphogranuloma venereum, trachoma, inclusion conjunctivitis, and
uncomplicated urethral, endocervical, or rectal infections in adults
caused by Chlamydia trachomatis
When bacteriologic testing indicates appropriate susceptibility to
the drug, doxycycline may be used to treat these infections caused by Gram-negative bacteria:
Some Gram-positive bacteria have developed resistance to doxycycline. Up to 44% of Streptococcus pyogenes and up to 74% of S. faecalis specimens have developed resistance to the tetracycline group of antibiotics. Up to 57% of P. acnes strains developed resistance to doxycycline.
When bacteriologic testing indicates appropriate susceptibility to the
drug, doxycycline may be used to treat these infections caused by Gram-positive bacteria:
Upper respiratory infections caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae)
Doxycycline may also be used as adjunctive therapy for severe acne.
The first-line treatment for brucellosis is a combination of doxycycline and streptomycin and the second-line is a combination of doxycycline and rifampicin (rifampin).
Antimalarial
Doxycycline is active against the erythrocytic stages of Plasmodium falciparum but not against the gametocytes of Plasmodium falciparum. It is used to prevent malaria.
It is not recommended alone for initial treatment of malaria, even when
the parasite is doxycycline-sensitive, because the antimalarial effect
of doxycycline is delayed.
The World Health Organization
(WHO) guidelines state that the combination of doxycycline with either
artesunate or quinine may be used for the treatment of uncomplicated
malaria due to Plasmodium falciparum or following intravenous treatment of severe malaria.
Antihelminthic
Doxycycline kills the symbioticWolbachia bacteria in the reproductive tracts of parasiticfilarialnematodes, making the nematodes sterile, and thus reducing transmission of diseases such as onchocerciasis and elephantiasis. Field trials in 2005 showed an eight-week course of doxycycline almost completely eliminates the release of microfilariae.
Spectrum of susceptibility
Doxycycline
has been used successfully to treat sexually transmitted, respiratory,
and ophthalmic infections. Representative pathogenic genera include Chlamydia, Streptococcus, Ureaplasma, Mycoplasma, and others. The following represents MIC susceptibility data for a few medically significant microorganisms.
Subantimicrobial-dose
doxycycline (SDD) is widely used as an adjunctive treatment to scaling
and root planing for periodontitis. Significant differences were
observed for all investigated clinical parameters of periodontitis in
favour of the scaling and root planing + SDD group where SDD dosage
regimens is 20 mg twice daily for 3 months in a meta analysis published
in 2011.
Contraindications
Pregnancy and lactation
Doxycycline is categorized by the FDA as a class D drug in pregnancy. Doxycycline crosses into breastmilk.
Other tetracycline antibiotics are contraindicated in pregnancy and up
to eight years of age, due to the potential for disrupting bone and
tooth development.
They include a class warning about staining of teeth and decreased
development of dental enamel in children exposed to tetracyclines in
utero, during breastfeeding or during young childhood.
However, the FDA has acknowledged that the actual risk of dental
staining of primary teeth is undetermined for doxycycline specifically.
The best available evidence indicates that doxycycline has little or no
effect on hypoplasia of dental enamel or on staining of teeth and the CDC
recommends the use of doxycycline for treatment of Q fever and also for
tick-borne rickettsial diseases in young children and others advocate
for its use in malaria.
Adverse effects are similar to those of other members of the tetracycline antibiotic group. Doxycycline can cause gastrointestinal upset.
Oral doxycycline can cause pill esophagitis, particularly when it is
swallowed without adequate fluid, or by persons with difficulty
swallowing or impaired mobility. Doxycycline is less likely than other antibiotic drugs to cause Clostridium difficile colitis.
An erythematous
rash in sun-exposed parts of the body has been reported to occur in
7.3–21.2% of persons taking doxycycline for malaria prophylaxis. One
study examined the tolerability of various malaria prophylactic regimens
and found doxycycline did not cause a significantly higher percentage
of all skin events (photosensitivity not specified) when compared with
other antimalarials. The rash resolves upon discontinuation of the drug.
Unlike some other members of the tetracycline group, it may be used in those with renal impairment.
The combination of doxycycline with dairy, antacids, calcium supplements, iron products, laxatives containing magnesium, or bile acid sequestrants is not inherently dangerous, but any of these foods and supplements may decrease doxycycline's effectiveness.
Breakfast was observed to reduce doxycycline absorption
significantly. Absorption of tetracycline occurs in the stomach and the
upper small intestine. Absorption of tetracyclines has been reported to
be impaired by milk products, aluminum hydroxide gels, sodium
bicarbonate, calcium and magnesium salts, laxatives containing magnesium
and iron preparations. The mechanisms responsible for decreased
absorption appear to be chelation and an increase in gastric pH. ... In
view of these results, it is advisable to instruct the patients to take
doxycycline on an empty stomach.
Previously, doxycycline was believed to impair the effectiveness of many types of hormonal contraception due to CYP450
induction. Research has shown no significant loss of effectiveness in
oral contraceptives while using most tetracycline antibiotics (including
doxycycline), although many physicians still recommend the use of
barrier contraception for people taking the drug to prevent unwanted
pregnancy.
Pharmacology
Doxycycline, like other tetracycline antibiotics, is bacteriostatic. It works by preventing bacteria from reproducing through the inhibition of protein synthesis.
Doxycycline is highly lipophilic so can easily enter cells,
meaning the drug is easily absorbed after oral administration and has a
large volume of distribution. It can also be re-absorbed in the renal
tubules and gastrointestinal tract due to its high lipophillicity so has
a long elimination half life, and does not accumulate in the kidneys of
patients with kidney failure due to the compensatory excretion in faeces.
Doxycycline–metal ion complexes are unstable at acid pH, therefore more
doxycycline enters the duodenum for absorption than the earlier
tetracycline compounds. In addition, food has less effect on absorption
than on absorption of earlier drugs with doxycycline serum
concentrations being reduced by about 20% by test meals compared with
50% for tetracycline.
Mechanism of action
Doxycycline
is a broad spectrum antibiotic. It inhibits the synthesis of bacterial
proteins by binding to the 30S ribosomal subunit, which is only found in
bacteria.
This prevents the binding of transfer RNA to messenger RNA at the
ribosomal subunit meaning amino acids cannot be added to polypeptide
chains and new proteins cannot be made. This stops bacterial growth
giving the immune system time to kill and remove the bacteria.
Pharmacokinetics
The substance is almost completely absorbed from the upper part of the small intestine. It reaches highest concentrations in the blood plasma after one to two hours and has a high plasma protein binding rate of about 80–90%. Doxycycline penetrates into almost all tissues and body fluids. Very high concentrations are found in the gallbladder, liver, kidneys, lung, breast milk, bone and genitals; low ones in saliva, aqueous humour, cerebrospinal fluid (CSF), and especially in inflamed meninges. By comparison, the tetracycline antibiotic minocycline penetrates significantly better into the CSF and meninges.
Doxycycline metabolism
is negligible. It is actively excreted into the gut (in part via the
gallbladder, in part directly from blood vessels), where some of it is
inactivated by forming chelates. About 40% are eliminated via the kidneys, much less in people with end-stage kidney disease. The biological half-life is 18 to 22 hours (16±6 hours according to another source) in healthy people, slightly longer in those with end-stage kidney disease, and significantly longer in those with liver disease.
Chemistry
Expired
tetracyclines or tetracyclines allowed to stand at a pH less than 2 are
reported to be nephrotoxic due to the formation of a degradation
product, anhydro-4-epitetracycline causing Fanconi syndrome. In the case of doxycycline, the absence of a hydroxyl group in C-6 prevents the formation of the nephrotoxic compound.
Nevertheless, tetracyclines and doxycycline itself have to be taken
with caution in patients with kidney injury, as they can worsen azotemia due to catabolic effects.
After penicillin
revolutionized the treatment of bacterial infections in WWII, many
chemical companies moved into the field of discovering antibiotics by bioprospecting. American Cyanamid was one of these, and in the late 1940s chemists there discovered chlortetracycline, the first member of the tetracycline class of antibiotics. Shortly thereafter, scientists at Pfizer discovered terramycin
and it was brought to market. Both compounds, like penicillin, were
natural products and it was commonly believed that nature had perfected
them, and further chemical changes could only degrade their
effectiveness. Scientists at Pfizer led by Lloyd Conover
modified these compounds, which led to the invention of tetracycline
itself, the first semi-synthetic antibiotic. Charlie Stephens' group at
Pfizer worked on further analogs and created one with greatly improved
stability and pharmacological efficacy: doxycycline. It was clinically
developed in the early 1960s and approved by the FDA in 1967.
As its patent grew near to expiring in the early 1970s, the patent became the subject of lawsuit between Pfizer and International Rectifier that was not resolved until 1983; at the time it was the largest litigated patent case in US history.
Instead of a cash payment for infringement, Pfizer took the veterinary
and feed-additive businesses of International Rectifier's subsidiary,
Rachelle Laboratories.
In January 2013, the FDA reported shortages of some, but not all,
forms of doxycycline "caused by increased demand and manufacturing
issues". Companies involved included an unnamed major generics manufacturer that ceased production in February 2013, Teva (which ceased production in May 2013), Mylan, Actavis, and Hikma Pharmaceuticals.
The shortage came at a particularly bad time, since there were also
shortages of an alternative antibiotic, tetracycline, at the same time.
The market price for doxycycline dramatically increased in the United
States in 2013 and early 2014 (from $20 to over $1800 for a bottle of
500 tablets), before decreasing again.
Society and culture
Doxycycline is available worldwide under many brand names. Doxycycline is available as a generic medicine.
Doxycycline and other members of the tetracycline class of antibiotics are often used as research reagents in in vitro and in vivo
biomedical research experiments involving bacteria as well in
experiments in eukaryotic cells and organisms with inducible protein
expression systems using tetracycline-controlled transcriptional activation.
The mechanism of action for the antibacterial effect of tetracyclines
relies on disrupting protein translation in bacteria, thereby damaging
the ability of microbes to grow and repair; however protein translation
is also disrupted in eukaryotic mitochondria impairing metabolism and leading to effects that can confound experimental results. Doxycycline is also used in "tet-on" (gene expression activated by doxycycline) and "tet-off" (gene expression inactivated by doxycycline) tetracycline-controlled transcriptional activation to regulate transgene expression in organisms and cell cultures. Doxycycline is more stable than tetracycline for this purpose. At subantimicrobial doses, doxycycline is an inhibitor of matrix metalloproteases, and has been used in various experimental systems for this purpose, such as for recalcitrant recurrent corneal erosions.
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