The Post Antibiotic Era will take your job away.

In 1934, The Los Angeles Milk Commission gave its employees devastating ultimatum- lose their tonsils or lose their jobs. When our antibiotics stop working, your employer may force you to make a similar choice; and they'd be right.

Infectious bacteria are developing resistances to our medicines at alarming rates, and we are entering a Post-Antibiotic Era. If you want to know how people will cope in this new era, the best place to look is in the past. In the era before antibiotics.

 In the early 1930's, scarlet fever and strep throat were much more common than they are today, and much more hazardous. In the worst case scenario, a sore throat could develop into full blown sepsis.

So when a report was published in 1931 describing 71 outbreaks of this disease that could be traced to one common factor, people paid attention. That common factor was milk contaminated with bacteria named Streptococcus epidemicus. These bacteria tended to infect the udders of cows, causing mastitis. Since the udders also happen to be where the milk was produced, bacteria inevitably spread to the milk.

Needless to say, these outbreaks needed to be brought under control.

That responsibility fell to the Los Angeles Milk Commission,  implemented a number of rules to prevent any more outbreaks occurring.

The first step was to find any dairy cows infected with the disease. Fortunately, there were already rules in place for this. Cows needed to be certified to be free of S. epidemicus, and any infected cows needed to be isolated from the rest of the herd.

Here is the problem. Both humans and cows could carry S.epidemicus. To control any outbreaks, the same restrictions that applied to cows had to apply to the humans who worked with them. Humans could carry S. epidemicus without any symptoms, and appearing perfectly healthy.

Out of a thousand employees tested, fifty were carriers. This was devastating. They could no longer be allowed to work, for the risk of them causing an outbreak was unacceptable. 

There were no available antibiotic treatments to allow these carriers to rid themselves of S.epidemicus, but that didn't mean there were no options. It was known at the time that S. epidemicus survived in human tonsils. If the tonsils were removed, then the bacteria would have nowhere to go, and die off.

In a quote from the Director of the milk commission:

"care is taken in each case to impress upon them that the procedure is not compulsory except that otherwise they must retire from employment at certified dairies"

Basically, the procedure was only compulsory if the workers wanted to keep their jobs.

Unsurprisingly, most of the workers chose to go through the operation.

But sixteen of the infected employees either refused to go through with it, or were refused on the basis of underlying health issues that could render such an operation life threatening. These people were forced out of their jobs, and any dairy in the area was given their details should they attempt to apply for another job in the milk industry. Essentially, they were blacklisted from the industry.

You can say it was cruel that employees were forced into this situation, and you're not wrong. But it was an awful dilemma, and one that is destined to repeat. In a world without antibiotics, people who become carriers of diseases may remain carriers for the rest of their lives. Through no fault of their own, these people will pose a threat to the rest of the population, and it will hurt their chances of working in certain jobs. Would you send your kid to a school where a teacher constantly infects their students with life threatening illness ? Or buy groceries from a man with chronic diarrhoea? Allow yourself to get treated by Typhoid Mary?

 None of those sixteen workers ever suffered any symptoms. They may spent their life working in the dairy industry, only to be cast aside. They at least had the option of getting surgery to prevent them from being carriers. Not all bacteria are polite enough to live solely within an easily removed organ. 

The Post-Antibiotic Era is coming, and it won't just affect "sick" people, it will have wider effects throughout society. If there is one lesson we can learn from this eighty year old paper, it is that you don't even have to be "sick" for bacteria to ruin your life.

*Streptococcus epidemicus is a defunct classification that tends to be refer to what would be called S. zooepidemicus these days, and S. pyogenes.

Bonynge C.W. (1934). Solution of the Streptococcus Carrier Problem *†, American Journal of Public Health and the Nations Health, 24 (10) 1031-1034. DOI: 10.2105/AJPH.24.10.1031

History of Bacteriology: Miasmas and Contagions

Have you ever found yourself walking down a street, and be confronted with a pungent turd blocking your path?

You don't know where it came from, but whether it be a dog or a tramp, you know to avoid it. It's a natural instinct. Toiletry behaviour can be found all over the natural world. Even tree sloths will make the effort to climb down to defecate far away from where they feed. The disgusting odours we associate with putrefying meat, faeces and death are ones we naturally try to avoid, and when that isn't possible we try to cleanse ourselves thoroughly so that we don't have to experience their stench.

If you were to ask me where the Miasma theory came from, I would point not to any one individual, but to that instinct of disgust. It was it's link to this natural response that also made it so difficult for people to dismiss miasmas even when confronted with overwhelming evidence that they didn't exist.

Many peoples across the world developed their own culture of hygiene and cleanliness, which usually involved some form of cleaning ritual and disposal of waste.
Often, these traditions would propose a specific association between bad smells and disgusting objects with disease. Across the world, incense and pungent smelling products tended to be used for treatments. Getting rid of the smell equated to getting rid of the disease.
Hippocrates advised people to stay away from places with "bad air" in many of his writings, and expounded the earliest iteration of the Miasma theory. His work was translated into multiple languages and passed through the ancient world, forming the basis of medical practice for centuries after his death. The concept of "Bad air" being the cause of diseases became well established. But it was not the only theory of disease people used.
In 1546, Girolamo Fracastoro published "De Contagione et Contagiosis Morbis", where he wrote about the "Contagion" theory of disease. He drew together various observations on disease that he had accumulated over his forty year long career as a physician. He proposed that diseases could be caused by the transfer of some imperceptible, yet corrupt matter between the sick and the well.  He called this corrupt matter "the seeds of contagion". He proposed that these seeds could spread in three distinct ways. Through direct contact with infected people, through contact with inanimate objects that had been in contact with sick people (he named these "Fomites") and at a distance. He connected these seeds to "putrefaction", in that they could cause it in their hosts, explaining diseases such as gangrene. His explanations generally attempted to reconcile contagion with Hippocratic theories that all diseases were caused by imbalances between four mysterious "humours" found within the body. The types of disease would be determined by which particular humour interacted with specific seeds.
His work sparked off as debate throughout Europe. Whilst the idea of contagion became more widely known, there was much debate over its theoretical causes and his interpretation of the work of Galen and Aristotle and objection over creating a whole new form of life, these seeds, out of thin air.  Fracastoro's most fierce critic was one of the first converts to contagion, Giambattista da Monte. The two would continually clash over the differences in their ideas, a hostile relationship that would eventually develop into one of mutual respect. The students who were privy to these lectures came from all over Europe, and when they returned to their home countries, they would bring the theory of contagion with them.
When proponents of "Bad Air" theory heard of the contagion theory, sparks most conspicuously did not fly. There were arguments, but they were no less vicious than the ones going on between the people who accepted contagion as a theory. Contagion theory still accepted that diseases could be caused by "Bad Air", but that the reason for this was that the air was filled with the "seeds of disease". "Bad Air" Theory held that sufferers of disease were primary sources of "Bad air", and people could catch disease from close contact with the sick.
However, the "Bad Air" theory got a boost in the 17th century when the Hippocratic corpus began to be re-evaluated by a number physicians. I've already talked about a gentleman named Thomas Sydenham who was key for bringing the Hippocratic corpus into the English language and kick starting a new era in evidence based medicine. He lived in an era where doctors applied many treatments based on theoretical ideas, such as bloodletting, sweating and forcing patients to vomit in order to "balance the humors". Sydenham however recognised that many of these treatments did more harm than good, and that the only way to truly divine a theory of medicine would be by a patients bedside.
Unfortunately, he did not have access to the fabulous microscopes of Anton Leeuwenhoek (No-one did, Leeuwenhoek was incredibly protective of his work) so he had no way of determining an evidence basis for contagion. In the end, he tended to favour Hippocratic theories of "Bad air" being the cause of disease, as he had no evidence available to prove otherwise.
In a treatise about malaria* written by Giovanni Maria Lancisi called "On the Noxious Effluvium of Marshes"he connected the disease with the noxious smells emanating from marshes and the mosquitoes that live within them. He gave a name to these noxious smells, he was the first to call them "Miasmas".
The Contagion theory and the Miasma theory were no longer seen as compatible by a growing number of physicians.
His writings went global, and were of particular influence in the United States on medical professionals such as Noah Webster and Benjamin Rush. During an outbreak of Yellow Fever in Philadelphia, many suspected that it had arrived from a contaminated consignment of Coffee from a ship with a crew riddled with the disease. However, Benjamin Rush disagreed with this vehemently, suspecting it had come from the marshy miasma's he believed surrounded the city. Even though Rush believed that contagion played a role in these early cases, that belief eventually waned. By 1799 he actively protested against quarantine procedures for sailors entering the city. By 1805 he began writing treatises to dismiss the idea of contagionism.
Maritime Quarantine procedures were a problem the world over, and cut into the business of many growing companies. It was in the interests of these companies to fuel the backlash against Contagionism.
When quarantine procedures** failed to prevent the Liverpool Cholera epidemic, a major blow was struck to the theory. The Cholera Riots demonstrated the true chaos which could follow a disease epidemic, and spurred people to enact new precautions against these outbreaks. These precautions would be based on the theory of Miasma.
Edwin Chadwick was a major supporter of the Miasma theory, and a vehement anti-contagionist. . He was aware that often, Cholera was associated with unsanitary conditions, and he realised that if the Miasma theory was true, then the greatest threat to peoples health was the presence of open sewers within cities. Through his efforts, open sewers were eliminated, and the cleaning of the streets began to be seen as an issue of public health. These massive clean-up efforts were incredibly effective, and would fuel further support for Miasma theory.
As we now know, Miasma's do not exist, at least not in the form that most people believed in at the time. There are solid reason why humans developed an aversion to particular bad smells. Often the sources of these smells would contain harmful diseases. Clearing out sewage from cities helped people because it meant that flies that fed on faeces could not then transfer microbes from those faeces onto food. It removed opportunities for bacteria such as typhoid from spreading through the streets in shit.
Whilst Chadwick's reforms produced results, they still had problems that are a lot more obvious to modern readers. Whilst the sewers were covered, they still discharged into the water supply, which caused regular outbreaks of cholera and typhus within the city.
Nevertheless, the Miasma Theory had risen to prominence by the 1830's, and its supporters would often define themselves as "anti-contagionist".
But the picture, as always, is more complex. Contagionism, whilst under attack, was far from dead.

*The very name "Malaria" refers to the bad air theory, with "Mal" meaning bad and "Aria" referring to the air. Although it didn't necessarily just refer to our modern interpretation of the disease. Many sweating sicknesses similar to what we understand as malaria would be referred to by its name as well.
** No-one knew of the waterborne nature of the disease, and nor was it thought that fomites could have played a role.

References

Curtis V.A. (2007). Dirt, disgust and disease: a natural history of hygiene, Journal of Epidemiology & Community Health, 61 (8) 660-664. DOI: 10.1136/jech.2007.062380

Nutton V. (1990). The Reception of Fracastoro's Theory of Contagion: The Seed That Fell among Thorns?, Osiris, 6 (1) 196. DOI: 10.1086/368701

Ayliffe G.A.J, English M.P. (2003) Hospital Infection: From Miasmas to MRSA, Cambridge University Press. Link

History of Bacteriology: The Cholera Riots

Murmurs of murder rippled through the crowd as it accumulated outside the entrance of the building, cursing the people who entered and exited it. They had watched helpless woman stretchered into the building, knowing she would soon join of the hundreds of people who had died within its walls. Whole city of Liverpool was in uproar, and had endured enough.

History does not record who threw the first stone, but soon the air was thick with them. They thudded against the buildings wall's, breaking the windows and scattering the people within. The men and women escaping the building were chased and beaten. 

The building was Toxteth Park Hospital, the people being chased were Doctors and nurses, and this was the beginning of the Liverpool Cholera Riots.

It was the age of the Industrial Revolution, Empire and Mass migration. Irish immigrants formed a major part of this migration, travelling to America to avoid the depredations back home. The primary intersection between the British Isles and America was a Liverpool. Immigrants awaiting passage to the new world would often find themselves stuck in the overcrowded city of Liverpool.

Like many cities of this era, Liverpool was transforming into a haven of squalor and disease. Urine and faeces were flung freely into the streets where they flowed into the rivers from which people drank. Tuberculosis and Typhoid ravaged the poor.  

The industrialization of Europe had meant that transport links had become much quicker, and trade had improved, but brought with it diseases. Rags from continental hospitals sold to farmers in Yorkshire to help manure hops also carried with them a disease that had not been seen in England before. It was known as "Asiatic Cholera" * at the time, and it frightened the rich and poor alike. Before its appearence, "Cholera" had only referred to seasonal stomach bugs and diarrhoea, and didn't relate to the deadly bacterium which we now refer to as Vibrio cholerae.

The month after the infected rags had been imported into Hull, the first cases of Cholera began to be recorded. Patients suffered from diarrhoea, severe cramps, followed by severe dehydration and then death, with the final symptom being the patients turning blue. It could turn a healthy person into a corpse within twenty four hours.

In 1831, an epidemic devastated Sunderland, killing over 20,000 people. The doctors could not contain the outbreak, their treatments consisting of brandy, bleeding and opium. Fear of this disease was high when it reached Liverpool in 1832.

A veteran medic who had experienced Cholera first hand whilst stationed in India tried his best to calm the situation. After the first two cases reported in Liverpool, he publicly stated that this "was not the case of an epidemic" like people may have heard about in Europe or Dublin. Not long after this, Cholera broke out on a vessel named the Brutus, claiming eighty-one deaths. Liverpool's Board of Health were slow to act, at first apparently denying the news of the outbreak within their city. At the boards very outset it was criticised as being filled with "a few fat-bellied magistrates" who had obtained their position through patronage rather than any medical expertise. Their sluggish reaction to this epidemic did not help that public perception.

The hysteria surrounding this disease was only rivalled by the scandal surrounding the whole medical profession. In the early half of this century, medical schools suffered from a dearth of human cadavers for students to practice on, and had begun to pay quite handsomely for them. In Edinburgh, two enterprising gentleman by the names of Burke and Hare decided to capitalise on this need by making a few corpses of their own, killing 16 people and making approximately £8K in today's money. The complicity of the medical establishment in this case combined with widespread reports of grave-robbing and the publics general distaste for dissection stained the medical establishment. People were now well aware of the high prices doctors would pay for a good corpse. A patient walking into a doctors surgery may have worried that they could be worth more dead than alive.

When Cholera began to spread through Liverpool people began to refer to doctors as "Burkers", invoking the more notorious of the murderers and implying that doctors were profiting from the deaths of their patients. 

The medical board in the meantime were doing their best to contain the disease, setting up new hospitals for patients to go to, and arranging carts to carry sufferers to these hospitals. The doctors and nurses worked hard to help their patients, but were severely hampered by the fact that none of their treatments appeared to work. In fact, it is likely that treatments like bloodletting made the disease a lot more dangerous.

Things however came to a head when Mr Clarke and his wife fell ill from Cholera. The doctors were jeered at by the mob when they brought the woman into the building. At this point the Liverpool Chronicle picks up the story.

“Stones and brickbats were thrown at the premises, several windows were broken, even in the room where the woman, now in a dying state, was lying, and the medical gentleman who was attending her was obliged to seek safety in flight. Several individuals were pursued and attacked by the mob and some hurt."

 The next few days saw the protests escalate. Mobs prevented doctors from carrying away their patients by any means necessary. They would halt the palanquins that were used to carry patients away, and when that didn't work they started to smash them to pieces. In one incident, people opted to hide a patient away from a surgeon tasked with treating her, and upon confronting them is chased across town to take refuge in a shop. Nightly gatherings surrounded the hospital in Toxteth Park. The police were often called in to hold back the worst excesses of the violence, but were simply overwhelmed.

But it wasn't just the fear of the doctors that motivated people. Cholera hospitals were rapidly being set up, bringing sick people to places of business. Some of those in the crowd wanted the doctors to take their grisly business elsewhere. Conspiracy theories abounded about how doctors were perpetuating the epidemic for a £10 "cholera fee" paid out by local bureaucrats. In some cities, Grocers believed doctors were advising people from staying away from certain food, leading them to be pelted with fruit.

The riots in Liverpool were solved when a threatening letter was sent to the mayor of the city. In the content of the letter, the author promised to do "wicked things" to any doctors who attempted to treat their patients. The author signed the letter off simply as "An Irishman". It was this last part of the message that suggested an alternative solution to the violence. Most of the cholera victims were the Irish Catholics crammed together within cramped underbelly of the city, and they were the loudest voices speaking out against doctors.

The Board of Health invited the Catholic clergy into a meeting to discuss solutions to the violence, and the clergy were given a message to deliver to their congregations. The speech addressed people fears about the cholera outbreak, and more importantly announced in no uncertain terms that the people who were dying were not being dissected. Furthermore, they declared that people had the right to go into the hospitals to see this for themselves, and to see the untouched bodies of their deceased before burial.

This was supported by an article published in the Liverpool journal by Dr James Collins , who also made a point of talking to people during church meetings. 

Soon, the streets of Liverpool were once again relatively quiet.

These riots occurred before anybody had a real handle on how infectious diseases spread. It was an era where the doctors had little idea of how to control a cholera outbreak, nor even what truly caused it. But the massive death toll and the incredible civil unrest spurred the government into action nonetheless. At this point, people had started to make the connection between overcrowding and poor sewerage to the spread of disease. The government would soon take steps to solving these problems, but in the process promote a troublesome theory that nearly strangled the nascent science of microbiology in its crib.

References

Burrell S. & Gill G. The Liverpool cholera epidemic of 1832 and anatomical dissection--medical mistrust and civil unrest., Journal of the history of medicine and allied sciences, PMID: 16144959

Puntis J. 1832 cholera riots., Lancet, PMID: 11597715

Gill G., Burrell S. & Brown J. Fear and frustration--the Liverpool cholera riots of 1832., Lancet, PMID: 11476860
Howie W.B. (1981). Stephen T. Anning, The history of medicine in Leeds, Leeds, W. S. Maney, 1980, 8vo, pp. ix, 218, illus., [no price stated], (paperback)., Medical History, 25 (04) 442-443. DOI: 10.1017/S002572730003502X

Further Reading

The First Spasmodic Cholera Epidemic in York, 1832, Issues 37-46 By Michael Durey

* The only doctors who had observed it were those who had been serving in the armed forces in the Empire when this disease swept through India during the Kumbh Mela, hence why it is known as Asiatic Cholera. A second pandemic had been working its way across Europe.

History of Bacteriology :The Rebirth of Microscopy

It was Robert Hooke who first popularised microscopy when he published his seminal work in "Micrographia". He had produced exquisite images of the eye of a fly, of tiny fleas, and of the tiny structures within a cork plant, naming them "cells". However, within five years of its publication, many of its findings were overshadowed by the work of a  mysterious Dutchman.

 The Dutchman in question was a successful garment seller who had developed a keen interest in Microscopy. In his workshop he had quietly begun to develop some of the most advanced microscopes of his era. This man was Anton Leeuwenhoek, and is often credited as the "Father of Microbiology". 

He created the first microscope powerful enough to see the Microbes. He could see organisms too small to be visible to the naked eye, and stunned the world with his intricate drawings of these tiny creatures. He was the first person to discover the existence of single celled organisms, and his regard spread throughout Europe.
 Robert Hooke became a massive fan of Leeuwenhoek, and a supporter of his work. He had but one problem. The entire field of microscopy was "Reduced to a single Votary, which is Mr Leeuwenhoek". Whilst the world was filling with astronomers, mathematicians and naturalists, there was only one person who was looking into the tiny world of single celled organisms.

Why was Anton van Leeuwenhoek the only microscopist left in the world ?   

Hooke believed that it was the lack "of the inquisitive genius of the present age". i.e. no-one was interested in the subject.  But there were somewhat justifiable reasons why people weren't interested in microscopy.

 Leeuwenhoek was intensely defensive of his discoveries, fearing that some other may come along to take the credit. It was an understandable fear. Quite notably Robert Hooke had a long standing dispute with Newton over who discovered gravity first, and believed that Newton had purloined his ideas on the inverse square law and gravitational attraction*.

This is why Leeuwenhoek kept his methods secret, apprenticed no students, and refused to show anyone the microscopes he had used to make his discoveries. Leeuwenhoek's place in history was secured, but his legacy was not. 

When Leeuwenhoek died, he took microbiology with him. Whilst microscopes could be found in some places, they were merely curiosities with no practical function for those wanting to push the boundaries of science. They were incredibly difficult to use, and often produced distorted images, due in part to chromatic aberration. No-one knew how Leeuwenhoek got around these problems, and it would be a long time before anyone would create microscopes of comparable power.

Solving Chromatic Aberration
Lenses work by re-directing light into a focal point by taking advantage of light slowing down when it enters glass. Using shaped glass allows you to bend light, and focus it to magnify an image.

Each part of the wavefront entering the lens is slowed down, but because of the shape of the lens, they are all slowed down for different lengths of time, causing them to be distorted. This means that wavefronts coming out of the convex glass end up focused on one point.

This effect is the basis for telescopes, spectacles and your eye's ability to read the words I've just typed.

Here is the problem. Any optical material can split different wavelengths of light. This is what happens when we pass light through a prism, or when it goes through the raindrops to form a rainbow. The different wavelengths of light are slowed down to different speeds, which is what causes them to separate.
This effect is what causes chromatic aberration. 

Chromatic aberration causes multiple images of different colours to have different focal points. This results in blurry and miscoloured images. Leeuwenhoek's microscopes had sidestepped these problems by being incredibly small, and didn't suffer from chromatic aberrations due to the incredibly small distances involved.

It was an amateur optician named Chester Moores Hall who eventually solved the problem. The answer came to him as a result of his studies of the human eye. He noticed that the human eye itself had a spherical lens, so why wasn't human sight blighted with chromatic aberrations ?

He hypothesised that the jelly like vitreous humour in the eye held the answer. Somehow, the vitreous humour cancelled out the aberrations caused by the lens. He decided to use a similar method to compensate for the chromatic aberrations. He knew that some glasses would separate light in the opposite way to others. So if he used a type of glass that would naturally bend light the opposite way to the lens, he could use it to cancel out the splitting of light caused by chromatic aberration. He decided to use flint glass to form a cover over the lens, and theoretically correct for any aberration.

He had one big problem. He didn't know how to grind his own lenses. He needed to get someone to make his special lenses, but he didn't want any of them to figure out that he had solved chromatic aberration.
To keep his discovery secret, he used different lens-makers to make each part of his new invention separately. One would make the objective lens, and the other would make the corrective cover for it.
But Chester Moores Hall fell victim to an unfortunate coincidence. Neither of these lens makers could make the parts he requested, and both of them decided to subcontract the work onto a man named George Bass. When he constructed both of the primary parts for the lenses, he literally put the pieces together, and figured out what Chester Moores Hall had done.

George Bass mentioned this discovery to another optician, John Dollond, who had also been struggling with the same problem. Dollond immediately patented this discovery, and started selling corrective lenses that accounted for chromatic aberration.

It was his son, Peter Dollond,  who decided to fully enforce those patents. By this time, many other opticians around London were using chromatically corrected lens. Peter Dollond managed to use his fathers patent to try to run them out of business. In the subsequent legal proceedings, Dollond's competitors believed they had an ace in the hole. They called Chester Moores Hall to the stand, who confirmed that he was indeed the true inventor of the achromatic lens, giving them the right to dispute the patent.

The problem was that Chester Moores Hall kept it to himself, which became a major sticking point for the judge. The Judge ruled in favour of Dollond, because Dollond had tried to make a profit from his invention.

 It was a Dutch instrument maker named  Jan van Deijl who had managed apply achromatic lenses to microscopes. But he wanted to get them absolutely right, and spent such a long time perfecting them that the work had to be passed down to his son Harmanus, who would eventually publish that work and set up a company to start selling microscopes.  They suddenly became popular again, and scientists like Giovanni Amici and Joseph Jackson Lister* made further improvements to this design. Microscopy had been successfully rescuscitated.

Soon these instruments were in high demand, with microscope manufacturers popping up across Europe, and then across America.  They became the essential tools for naturalists and physicians, and microscopy became the forefront of important research during this era.

During the next month I will be writing a series of posts on the history of microbiology, focussing mostly on the massive leaps that happened during the 19th century. If I was to point at one reason why microbiology would finally came into its own during this era, I would point you to the microscope. Many of the greatest discoveries of this era simply would not have happened if these instruments had not become fixtures on the desks of reputable scientists around the world, waiting to be used.

References and Further Reading

Cassedy J.H. (1976). The Microscope in American Medical Science, 1840-1860, Isis, 67 (1) 76. DOI: 10.1086/351546

Dobell, Clifford (1932). Antony van Leeuwenhoek and His "Little Animals": being some account of the father of protozoology and bacteriology and his multifarious discoveries in these d

isciplines. New York: Harcourt, Brace and Company. 

Department of the History of Science (Harvard)  Description of Harmanus Van Deijl's compound microscope

Nineteenth-century Scientific Instruments by Gerard L'Estrange Turner

Peter Dollonds answers Jesse Ramsden -http://www.mhs.ox.ac.uk/sphaera/index.htm?issue8/articl5

* The impression I get from what I've read is that Robert Hooke, like many scientists of his era had come up with the rough idea that celestial bodies attract eachother, and that attraction dissipates with distance, but it was Newton who actually went ahead and created a mathematical model with a series of quantifiable laws to explain these phenomena. Hooke had the rough idea of what was going on, Newton had the detailed explanation.

** Not to be confused with his son, Joseph Lister, the pioneer of antisepsis.

Antibiotics & Agriculture Part 4: The Transfer of Antibiotic Resistance

The patient was in dire condition. A forty year old woman from Michigan, she had suffered badly from diabetes, kidney failure and a number of complications related to those diseases. Two years after she had started dialysis, disaster struck. She developed painful foot ulcers, and an infection in her leg that was so severe that the whole leg had to be amputated. What was worse was that immediately after the operation, her amputation wound became infected, with Staphylococcus aureus. In her only stroke of luck that day, the Staphylococcus aureus was susceptible to antibiotics. But the next year, the foot ulcers were back, and she required even more amputations, as well as treatments to prevent the bacterial infections causing these ulcers from becoming fatal.
The catheter that linked her blood to the hospital's dialysis machine, the replacement for her riven kidneys, provided Methicillin-Resistant Staphylococcus aureus with easy entry into her blood. There was only one antibiotic that could stop this MRSA infection. Vancomycin was given to the patient while the physicians removed the infected catheter. In its place, the physicians used a number of temporary catheters, to ensure that the patient could still use the dialysis machine.
But a number of these catheters also became infected. When the physicians examined these catheters, they realised that against all odds, things had taken a turn for the worse. They discovered that the Staphylococcus aureus on this catheter had been joined by Vancomycin resistant Enterococci. Now the Staphylococcus aureus were resistant to Vancomycin too.  They searched all of the possible options that could have lead to this situation, and it was the DNA evidence that revealed what had happened. The Vancomycin resistant Enterococci, commonly found in the community but rarely infectious, had given its resistance genes to MRSA.

This was the first of a series of outbreaks of VRSA that occurred in Michigan, and all of them had a similar theme. A person with an MRSA infection would spontaneously develop full blown resistance to vancomycin out of nowhere. The only commonality in all of these cases was the presence of vancomycin resistant Enterococci both before and during these cases. So how did vancomycin resistant Enterococci pass along their resistance to MRSA ?
The answer lies with DNA molecules known as plasmids.

 These are rings of DNA which can carry genes between different bacteria. The exchange of plasmids between bacteria is a key driver of bacterial evolution, as it allows species to share genes between eachother. They enable bacteria to acquire new traits from other bacteria in the vicinity, which can allow them to adapt to their environment in new ways. In this case, the vancomycin resistance "trait" was carried on a plasmid in Enterococci, and this plasmid could be very easily transferred to Staphylococcus aureus.  The high abundance of Enterococci with vancomycin resistance increased the probability of this occurring.

This constant transfer of plasmids between bacteria plays a key role in their evolution. It allows a bacterium entering a new environment to steal some useful genes from the bacteria that are already there, helping it adapt to that niche. This is what happened in the cases discussed above, and is one of the more insidious methods through which antibiotic resistance can spread.
As we've seen in the previous posts, the unregulated use (and in some cases regulated use) of antibiotics in agriculture leads to the evolution of new resistant strains of bacteria. These strains can exchange this resistance using plasmids. The transfer of these plasmids to human pathogens is a major threat to human health.

Making things worse is that some plasmids can carry multiple resistance genes, rendering a variety of different antibiotics useless. The problem with using antibiotics in agriculture comes primarily from increasing the net amount of these non-pathogenic bacteria with resistance genes.

In the above case study, we have seen that Enterococci can exchange its resistance with Staphylococcus aureus. But we only know about Enterococci because on rare occasions, they can cause disease in humans. We don;t keep a track of all of the bacteria that don't cause disease. These are the bacteria that live in our bodies, that help us digest food and maintain an immune system. we are constantly exchanging these bacteria with our environmental surroundings.
 They live under the radar, and nobody notices when they develop antibiotic resistance. Since they never cause disease in humans, we never need to prescribe antibiotics against them. The only time they would encounter sustained levels of antibiotics is on a farm, where they are constantly infused into the feeds of their animal hosts. Here they can evolve new resistances, and when they get transferred to humans, can exchange their antibiotic resistances with the bacteria they find in their new niche.
It is difficult for us to tell what kind of resistances an invading pathogen could potentially pick up from these bacteria.
To use an analogy, these silent bacteria may act as weapons merchants, hoarding resistances until the can share them with one of our potential enemies.
One way for researchers to investigate this is to simply take a snapshot of bacteria within an area, and just test for the resistance genes. Instead of looking for the weapons merchants, they are focussing on checking for the weapons.
 With this technique, the scientists directly checked for the presence of resistance genes in an environment. This is known as the “resistome”.
Recently a group of researchers took it upon themselves to catalogue the “resistome” of three different countries.  They compared the types of resistances they found in different countries to the way antibiotics were used in each of them.
The types of antibiotics that bacteria were resistant to were slightly different in each of the three countries they investigated (USA, Spain and Denmark). The antibiotics to which bacteria were most commonly resistant were the ones that were approved for use in animals. Antibiotic resistances were lowest in the places that had the ban in place for the longest time.
This all indicates that the agricultural use of antibiotics has contributed to the creation of a number of antibiotic resistant bacteria, but increased the number of resistance genes in our environment available for other pathogens to become resistant.
The mountain of evidence is indisputable. There is no doubt that new strains of antibiotic resistant bacteria owe their genesis to the reckless use of the drugs on farms. But is it fair for farms to take on the full brunt of the blame for the fall of antibiotics ? Would we not have antibiotic resistant bacteria in our hospitals even if the farms had banned them ?
I'll be dealing with this question in the conclusion of this series next time.

To be continued.....

References

Chang S., Sievert D.M., Hageman J.C., Boulton M.L., Tenover F.C., Downes F.P., Shah S., Rudrik J.T., Pupp G.R. & Brown W.J. & Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene., The New England journal of medicine, PMID: 12672861

Zhu W., Murray P.R., Huskins W.C., Jernigan J.A., McDonald L.C., Clark N.C., Anderson K.F., McDougal L.K., Hageman J.C. & Olsen-Rasmussen M. & (2010). Dissemination of an Enterococcus Inc18-Like vanA Plasmid Associated with Vancomycin-Resistant Staphylococcus aureus, Antimicrobial Agents and Chemotherapy, 54 (10) 4314-4320. DOI: 10.1128/AAC.00185-10

Forslund K., Sunagawa S., Kultima J.R., Mende D., Arumugam M., Typas A. & Bork P. (2013). Country-specific antibiotic use practices impact the human gut resistome., Genome research, PMID: 23568836

Antibiotics & Agriculture Part 3: The Spread of Resistant Bacteria

The application of antibiotics to livestock has provided a boon to the agricultural industry. Unfortunately an outbreak of Salmonella showed that this application could have some untoward side effects. The farmers and veterinarians not only failed to contain this outbreak of Salmonella, but botched the antibiotic treatment so thoroughly that a multi-drug resistant strain of this pathogen emerged and spread to humans.
Such was the outcry in response to this outbreak that the government set up the Swann report, which attempted to promote more responsible usage of antibiotics. Even though the 1964 outbreak was primarily a result of improper medication for farm animals, the use of antibiotic growth promoters emerged as a specific concern. One of the sole achievements of  this report was to separate the antibiotics used in humans to those used in animals, with specific restrictions on the use of antibiotic growth promoters.

Other countries experienced similar issues. An investigation in the US found that between 1971-1983, the majority of outbreaks of Multi-drug resistant Salmonella stemmed from contact with either farms or animal products. These antibiotic resistant Salmonella proved to be more lethal than their antibiotic sensitive counterparts. In 1977 the FDA decided that it was no longer safe to use certain antibiotics as growth promoters. They tried to stop front-line antibiotics such as penicillin and tetracycline being used as agricultural growth promoters. But for reasons that are unknown, they never followed up on their declarations. It is likely that the FDA simply didn't have the resources or the public support to pass such a law.

In contrast, Northern Europe had begun to implement restrictions on the usage of antibiotics in livestock. Often these restrictions consisted of allowing only one set of antibiotics for the agricultural industry and one for the medical community. But this soon encountered a major setback.
Clinicians began to encounter Vancomycin resistant strains of Enterococci. Vancomycin is often the drug of last resort, and was supposedly tightly regulated so as to prevent resistance developing. These outbreaks often occurred in hospitals, but not always.  When doctors examined patients to find out where this bacterium was coming from, they found something surprising. The source of these Vancomycin resistant Enterococci infections originated from the community. The doctors redoubled their efforts to work out the source of this infection. They checked farm animals, food from shops, sewage outflows, and any other possible place where Enterococci could hide.  What they found surprised them. They found this bacterium in farm animals and food sources and the sewage outflow. They found that not only were these hospital outbreaks traceable to these community sources, but there was a veritable reservoir of vancomycin strains out there that had not yet reached the hospital. But this presented a puzzle.
Vancomycin was only available to hospitals. In accordance with laws, the farms in the area were using different antibiotics. So why were these bacteria in the community, who should never have even seen Vancomycin, suddenly becoming resistant to it ?
The truth is that the bacteria had not specifically developed a resistance to Vancomycin. They had developed a resistance to a drug named Avoparcin. The vancomycin resistance was just a lucky side effect of this. You may not have heard of Avoparcin. This is because it was never meant to be used in humans. It was one of the few antibiotics allowed to be used as a growth promoter. What no-one had foreseen was that it's structure was so similar to vancomycin that it would breed resistance to it. And as a result, one of the key antibiotics to stop hospital outbreaks was rendered useless against the Enterococci.

But why should we worry about these bacteria. Enterococci aren't much of a threat outside of the hospital, and even then they tend not to have multiple drug resistances. Whilst we can worry about Salmonella, we should remember that the best ways of treating Salmonella  don't require antibiotics at all. So why should the spread of these antibiotic resistant bacteria be a worry for us ?

To Be Continued.....

References

Holmberg S., Wells J. & Cohen M. (1984). Animal-to-man transmission of antimicrobial-resistant Salmonella: investigations of U.S. outbreaks, 1971-1983, Science, 225 (4664) 833-835. DOI: 10.1126/science.6382605

Bates J., Jordens J.Z. & Griffiths D.T. (1994). Farm animals as a putative reservoir for vancomycin-resistant enterococcal infection in man, Journal of Antimicrobial Chemotherapy, 34 (4) 507-514. DOI: 10.1093/jac/34.4.507
O'Brien T. (2002). Emergence, Spread, and Environmental Effect of Antimicrobial Resistance: How Use of an Antimicrobial Anywhere Can Increase Resistance to Any Antimicrobial Anywhere Else, Clinical Infectious Diseases, 34 (s3) S78-S84. DOI: 10.1086/340244
http://docs.nrdc.org/health/files/hea_12032301a.pdf

Antibiotics & Animals Part 2: The First Warnings

In the previous post, we were wowed by the miraculous discovery that antibiotics could improve the growth and well being of farmed animals, such as pigs and baby chicks. The use of these growth promoters enabled farmers to save money on animal feed and improve the health of their animals. Soon, nearly 50% of all antibiotic sales went to the agricultural industry. Whilst there were some concerns over this unregulated use triggering the development of antibiotic resistant bacteria, without evidence these fell on deaf ears. This would soon change.

We begin this chapter of the story at the Enteric Reference laboratory. The job of this reference laboratory was to receive and catalogue samples of bacteria obtained from intestinal infections occurring around the country. It was during the 1960's that they began to receive samples from concerned farmers.
The environments on intensive farms of this era could best be described as overcrowded factories for disease. The farmers had noticed that calves were particularly prone to getting diarrhoeal infections. The bacteria causing these infections was Salmonella typhimurium, the bacterium responsible for human typhoid disease. This was not only a threat to the health of the herd, and those who interacted with them. Calves were dying. The Salmonella outbreaks needed to be brought under control. This is where it all started to go wrong.

There were two methods that were used to put a stop to Salmonella on these farms. The first method was to use high doses antibiotics to treat visibly sick cattle. The second method was to give lower doses of antibiotics to the rest of the visibly healthy herd, to prevent them getting ill. I say "visibly" because cows can carry Salmonella without showing any symptoms, so it is likely that plenty of the cows with Salmonella received the lower doses of antibiotic.
Unbeknownst to the veterinarians, they were creating the perfect environment for bacteria to develop resistance.
Antibiotic resistant strains began to make their first appearance in the beginning of 1963, when a strain developed resistance to sulfonamides and streptomycin.  A year later these bacteria had become resistant to six more antibiotics.

Soon, this multi-resistant strain of Salmonella began to spread to humans. The Enteric reference laboratory received over 500 samples of this same bacterial strain, obtained from human infections. The antibiotics that would normally used in these situations turned out to be useless. This outbreak provided dramatic evidence of the hazards of utilising antibiotics in agriculture. The UK government was forced into action

In 1969, the Swann committee convened to change the way we used antibiotics, so that this kind of outbreak would never be repeated. They recommended that a quasi-non governmental organisation (Quango) be created, which would act to oversee the use of antibiotics for both humans and animals. It was there to increase transparency, to make sure that people knew what antibiotics were being used for, and how much they were used. It would bring together the usage of both veterinary and medical antibiotics under one authority. This co-ordination would enable scientists to better understand the threat of resistance in all of its facets.
 Whilst the committee’s job was to regulate the use of antibiotics in both humans and animals, it ran into a number of problems. But the various different interest groups involved in antibiotics had no compulsion to co-operate. The committee had no real power to control the use of antibiotics, nor did it have any resources to investigate the impact of antibiotic overuse. Eventually it died a quiet death, having never quite lived up to the promise of its birth.

To be Continued Next Tuesday... Thursday...

Anderson E.S. (1968). Drug Resistance in Salmonella Typhimurium and its Implications, BMJ, 3 (5614) 333-339. DOI: 10.1136/bmj.3.5614.333

(1981). Death of a quango., BMJ, 282 (6274) 1413-1414. DOI: 10.1136/bmj.282.6274.1413-a

http://www.guardian.co.uk/society/2006/mar/22/health.science

Antibiotics & Agriculture Part 1: The Discovery of Growth Promoters

This story begins with Robert Stokstad, an agricultural scientist brought up on a Californian poultry farm . He had started his career fighting against malnutrition in chicks. He had found that a haemorraghic disease in chicks was in fact caused by malnutrition. He had followed this up by examining the diet of baby chicks, to work out which parts of the diet are the most essential, and which of those, if neglected could lead to disease. He was one of the first to discover that folic acid is an important component of nutrition in chicks, before people realised it’s importance for humans.

It was at Lederle pharmaceuticals, whilst working with Thomas Juke, that he made another significant discovery about the right things to feed baby chicks. He had found during his work that feeding chicks a diet of vegetables alone was not enough. In fact, many chicks would end up dying on this diet. If they were to survive, then some degree of animal protein was needed. Other people working in his field had found that adding a small amount of “sardine meal” to the mix helped this. But then in a later paper, those same researchers, Hammond and Titus, found that mixing in cow manure produced a similar effect. Yes, you read that right, there were people feeding chicks cow manure, and found that it was more healthy than feeding them a diet of just vegetables.

It was known at the time that vitamin B12 was a key factor needed for chicks to grow, and that often the vegetable diets given to these chicks did not have enough of it.  So Stokstad and Juke fed the chicks different mixtures of foods, and looked at how well they grew afterwards. One of the foods they included was a bacterium, Streptomyces aureofaciens, which they grew up and dried out and added to the feeds of the chicks. This was to work out why the cow manure turned out to be such a great dietary supplement. Stokstad knew that manure is full of bacteria, and that bacteria could produce B12. So the reason that cow manure was good for chicks was that it was a source of B12.

But Stokstad was not the sort to rule anything out. He decided to compare the potency of Streptomyces aureofaciens against B12 purified from liver extract. He found that the purified liver extract improved the growth of the chicks, nearly doubling their final weight. But when he fed the chicks Streptomyces aureofaciens , he discovered that they grew far faster and bigger than the ones fed with just the liver extract. This growth spurt was about more than vitamin B12. Streptomyces aureofaciens  was producing something else that was boosting the growth of these chicks. So what was this mysterious factor which made these chicks grow up so well ?

It was a compound known then as aureomycin, and it was amongst the first tetracycline antibiotics ever discovered. It was also one of the first antibiotic growth promoters. Other researchers were also beginning to discover the benefits of antibiotics in promoting the growth of animals. The use of antibiotics as feed additives caught on like wildfire.

One of the first to express their concerns over the growth of this industry was Robert Wrigglesworth, who in 1952 wrote a letter to the British Medical Journal

We have the prospect of more antibiotics being sold in the USA, as growth promoters for food in farm animals than are used for clinical medicine.

But at the time, these kinds of concerns were brushed aside, with some justification. So what if the bacteria that infect livestock become slightly resistant to antibiotics ? The bacteria that live within pigs and chicken don’t pose a problem to the health of people, because the only time that those aforementioned bacteria could possibly come into contact with us is after being thoroughly cooked. Right ?

 To Be Continued.....

References

  STOKSTAD E.L.R. & JUKES T.H. (1949). The multiple nature of the animal protein factor., The Journal of biological chemistry, PMID: 18135798

  Shane B. & Carpenter K. (1997). E. L. Robert Stokstad, Journal of Nutrition, (127) 199-201. DOI:

Wigglesworth R. (1952). Value of Organic Manures, BMJ, 1 (4772) 1357-1358. DOI: 10.1136/bmj.1.4772.1357-c

The Earlier discovery of Antibiotic Resistance

A couple of weeks ago, I wrote about how quickly penicillin resistance was discovered not long before it was distributed to the public, and how even Alexander Fleming noted his worries over penicillin resistance in the closing of his Nobel prize acceptance speech.

But even in the process of researching this article, I realised that I was merely scratching the surface. You see penicillin was not the first antibiotic discovered. If I want to talk about the first discovery of antibiotic resistance, then I will  need to tell this story as well.

In 1932 in Germany, a scientist patented an incredibly important discovery, one that would eventually win him the Nobel prize.

Domagk had been working at Bayer pharmaceuticals at the time of his discovery. In the early 1920's, Bayer had begun to experimenting with different methods for treating bacterial diseases. The experiences of World War 1 had left many researchers with the desire to find ways of preventing deaths from wound infections. Domagk had served in World War 1, and had worked in a cholera hospital near the eastern front. He noted the seeming futility of treating patients with infections. 

He came to the attention of Bayer pharmaceuticals after Professor Heinrich Hoerlein* had come across his thesis and decided to hire him. Hoerlein believed that dye molecules could be the key to solving bacterial infection.

The chemists at Bayer would synthesise new chemicals, and then send them to Domagk, and he would then test them on whether they could kill bacteria in vitro, or whether they could prevent mouse deaths from Streptococcus infection. Domagk managed to speed up this process to the point where he could test 30 new chemicals every week.

The chemist on the other end of this process was a man named Josef Klarer. He was the one rushing to make the chemicals for testing. He had tried a number of quinine derivatives, but had no luck. However, in 1932, things would change when he decided to make products based off of  Azo Dye molecules. His first success came with Kl-695**, which Domagk found to protect mice during an infection, even though it didn't seem to kill the bacteria in the petri dish. But based off of this finding, Klarer modified Kl-695 again and again. Until it came to a red dye compound that was at the time named Kl-730. 

Of course, even though this chemical had been proven in mice, it was as of yet unknown whether it would work in humans. But then Domagks daughter fell ill with a streptococcal disease, and desperate, he gave her a dose of the drug, curing her of the disease.

By 1935, Prontosil Red was being trialled internationally, with Leonard Colebrook, himself a frequent experimenter with antibiotics, demonstrating the effectiveness of Prontosil Red in treating pregnant women, albeit with the side effect of turning his patients bright red.  Prontosil Red was the first Sulphanilamide drugs.

Such was the success of this drug that he was nominated for a Nobel Prize in 1939. However, at this time the Nazi's were running Germany. They held a dim view of the Nobel prizes due to the previous German to win a prize. Carl von Ossietzky was a pacifist, who exposed the Nazi's breaking of the treaty of Versailles by training an air corp, and won the Nobel peace prize for his opposition to the Nazi's. As a result of this, the Nazi's forbade any German from accepting Nobel prizes

So when Domagk won a Nobel prize, he was immediately thrown in jail for a week by the Gestapo. This was enough to convince him not to accept the Nobel prize until 1947, two years after Fleming. 

By this time, Doctors were already discovering the limits of antibiotics. A.J. Cokkinis wrote in 1938 

Inadequate dosage and too short a period not only fail to do any good but seem to lead to the development of acquired resistance on the part of the organism to the drug

.

Amongst the first to analyse these limitations were a group of researchers based at St Mary's, one of whom was Alexander Fleming**. They had discovered that bacteria could adapt to antibiotic concentrations. The same year, Connor Macleod, a researcher based in New York, investigated this in more detail. He discovered that gradually increasing the amount of antibiotics in broth could increase the numbers of resistant bacteria.

Sulfa drugs like Prontosil Red changed the way medicine worked, and laid down the foundations upon which modern medicine would arise. Unlike penicillin, Prontosil and the related sulphonamide and sulphanilamide drugs could be created entirely synthetically from available chemicals. 

Bayer's technique for finding drugs could best be compared to throwing spaghetti against a wall until it sticks, testing random chemicals until they produced the effects they wanted. and people say that Alexander Fleming relied on luck ! Bayer appeared to be basing its company policy on it.

But the question remains as to why they decided to use dye compounds as antibiotics, how did they even know it could work. It's not like there was someone before them who discovered antibiotics even earlier...was there ?

To be continued tomorrow........

References
Wollheim Memorial- Phillip Heinrich Hoerlein
Bayer- Gerhard Domagk
Nobel Prize- Gerhard Domagk

Bentley R. (2009). Different roads to discovery; Prontosil (hence sulfa drugs) and penicillin (hence β-lactams), Journal of Industrial Microbiology & Biotechnology, 36 (6) 775-786. DOI: 10.1007/s10295-009-0553-8

Macleod C. & Daddi G. (1939). A ''Sulfapyridine-Fast'' Strain of Pneumococcus Type 1, Proceedings of the Society for Experimental Biology and Medicine, 41 69-71. DOI: 10.3181/00379727-41-10575P

Cokkinis A.J. (1938). SULPHONAMIDE CHEMOTHERAPY IN SURGICAL INFECTIONS--I, BMJ, 2 (4059) 845-847. DOI: 10.1136/bmj.2.4059.845


Gerhardt Domagk: The First Man to Triumph Over Infectious Diseases  By Ekkehard Grundmann

* Heinrich Hoerlein would eventually rise up to the managing board of IG farben, which was the conglomerate which ran a number of companies, including Bayer. Originally, it was primarily a dye making company. But it's activities during World War 2 were infamous. It was the company that developed Zyklon B, in the time that Hoerlein served on its board, which is why he found himself at the Nuremberg trials alongside many of the other company directors. It didn't help that at least one of these directors had been conducting experiments at Auschwitz under the direction of the SS. These experiments involved inducing artificial infections deliberately, and then giving the test subject antibiotics to cure the disease. Heinrich Hoerlein was amongst a number of IG Farbens executives who tried to stop the supply of these chemicals once he had found out what the Nazis were doing with them. When this came to light, the charges were dropped, but the reputation of IG Farben never really recovered, and the conglomerate didn't last long after the war, although some of it's constituent companies are still around today.

** Unfortunately the original paper is locked in the vaults of the Lancet, and so I am forced to diminish his role in the discovery of Antibiotic resistance, because there is no way for me to find out exactly what he did.

The Early Emergence of Antibiotic Resistance

The development of resistance to the antibiotics is a phenomenon of great theoretic interest to a bacteriologist, and it may some day become a matter of major concern to the clinician.

This is the opening line in C. Phillip Miller's paper on the development of resistance to antibiotics, which he published in 1947. Penicillin had only just been in production for five years. It was saving countless lives. It was emerging as a miracle drug. But even in this relatively optimistic era, a number of scientists were getting a taste of things to come.

History of Scarlet Fever: The Fight against Childbed fever, and it's many casualties

It was 1790,when Dr Alexander Gordon, a retired naval physician, decided to settle down in the scottish town of Aberdeen .  He had had an esteemed career , and a wide experience in treating malady.  So when the town was struck by a horrible epidemic, he was the man the local physicians looked to for guidance.
This epidemic of was of a very tragic kind. It affected mothers immediately after giving birth. This childbed fever was usually fatal.  The locals referred to it as weeds. Doctors tended to call this "puerperal fever" .This kind of fever has been recorded since the time of Hippocrates, and is referenced in the Ayurveda.  But it was never very common. But as the 19th century dawned, this disease became more common. The practice of midwifery was in flux as well. Historically, the main practitioners were women who had deep practical knowledge of their craft, but this was changing. Doctors and surgeons, backed by scholarship and a grounding in anatomy started to practive midwifery. Inventions such as obstetrics forceps revolutionised the field of midwifery. in the mid 1700s, "Lying in" maternity hospitals were established.
for this reason, Alexander Gordon would have been asked to preside over pregnancies as part of his general practice. Most doctors assumed that puerperal fever was a natural consequence of pregnancy, and paid it no mind.
Dr Gordon was different.  He did not have any pre-conceived assumptions about this disease. Much in the way as had been set out by Thomas Sydenham, he checked the facts before resorting to theory. He noticed that patients who succumbed to the disease tended to share contacts with eachother, or the midwives that tended to them. Through careful observation, he found that medical practitioners, including himself, were spreading contagion to their patients. In fact, he noted in his publication that the epidemic had not spread to a town outside of Aberdeen specifically because the midwife tending those areas had not become infected.  He was the first person to recognise that puerperal fever could be transmitted. And that the main medium of transmission was through doctors.

After making impassioned pleas for change, he was accused as being the cause of the outbreak. He was driven out of Aberdeen, and  eventually fell back into Naval service, where he would eventually die from tuberculosis far from home. His work was never fully conveyed to the medical establishment, and it faded into obscurity.
Nearly fifty years later, a doctor from Doncaster by the name of Robert Storr noticed a worrying trend in his patients. In the winter of 1840, there were outbreaks of scarlet fever and erysipelas. And suddenly, he noticed an epidemic of childbed fever.  More worryingly, he noticed that if he saw a pregnant woman soon after attending to a sufferer of childbed fever, they too would succumb to the disease. At these instances, he became incredibly anxious. He recognised the one factor that linked all of these patients: himself.
So he began a strict regimen of cleaning himself, and changing his clothes in between patients. So concerned was he that he decided to leave his practice, and take some time out in Wales, with the hope that the fresh air would help rid him of the "poison".
He returned to his practice, and to the treatment of his patients. Within a week of returning, he was called to attend to two pregnancies happening within a day of eachother. And both of those pregnancies resulted in the deaths of the mothers.
The good doctor was distraught. It was his colleague, Dr Thompson who suggested that perhaps Dr Storrs may have re-acquired the "poison" from another of the patients he saw. It was then that Dr Storr recalled that before each outbreak, he had attended one woman, a Mrs Richardson for erysipelas.
Erysipelas is another form of scarlet fever, a fact that had been recognised since the time of Daniel Sennert. In it's most severe form, it can manifest as necrotizing fasciitis. In the case of Mrs Richardson, it had caused massive build up of pus in her leg,  making it painful for her to move. Dr Storrs had been alleviating her pain it by draining off the pus. And Dr Storr realised that every time he attended a pregancy after draining off this pus, that pregnancy would lead to a case of fever.
He immediately handed over the treatment of Mrs Richardson to one of his colleagues, and found that his preventative measures began to work. And so he dug deeper. He asked around his medical colleagues, and found that many had similar experiences. One would note how doctors who attended mothers after dissecting corpses would often see those mothers die of childbed fever. And often, this fever would appear linked to cases of Erysipelas. He noted previous work had showed that it was possible to contract erysipelas from puerperal fever, and Storr realised that it could work both ways. He published his observations in the Provincial and Medical Journal. He was the first to realise that the disease of erysipelas, and scarlet fever was also the disease that was the cause of childbed fever. It was well read amongst the physicians of Britain, and soon other physicians came forward with their own stories.
Dr Francis Elkington of Birmingham wrote in support of Dr Storr, having noticed a similar pattern at his local practice in the preceding decade. He had begun to enforce strict hygienic practice when dealing with pregnant women, ensuring that he only wore clean clothes, and always cleaned himself. And as a result, for the past seven years, the numbers of patients who had died of childbed fever fell precipitously. There were only two cases. One happened when he was hurrying home after draining pus from a man by the name of Perry, and he was urgently needed for a woman who was "dangerously ill" and not supposed to be in labour. The second case happened at the house of Perry, where it was likely that he had transmitted the disease to the sufferer.
More physicians in Britain came forward, and soon Dr Storr found himself contacted by an American physician by the name of Oliver Wendell Holmes. He too had been investigating this problem for some time.

During a meeting of the Boston Society for Medical improvement, a peculiar case was discussed. A woman had died of childbed fever, and during the autopsy, the attending physician had sustained a wound. He soon developed Erysipelas, and died. It was said that in the week before he succumbed to this disease. It was said that before he had died, every pregnant woman to whom he had attended developed childbed fever. After fervent discussion, it was determined that more research was needed before they made any decisions as to how to change medical practice. One of the members in attendance, Dr Oliver Wendell Holmes, decided to take up this case. In 1842, he began to scour the literature, to see whether any other doctors had seen anything like this before.
What he found astonished him. He managed to find the first accounts by Dr Gordon published in 1795. As he interrogated the literature, he saw many more cases where physicians, upon suspecting themselves of "poisoning" their patients, enacting hygienic practices to prevent this happening again.
He catalogued a large number of cases, ranging over fifty years, and published his recommendations in the New England Quarterly Journal of Medicine and Surgery.
In England, Dr Storr seized upon this publication as further support for the guidelines he himself had been developing. However, Dr Storr's efforts in promoting these new guidleines ended abruptly with his death in 1847, due to fever.
 The New England Quarterly journal never got very much circulation, and Holmes's work only appeared in the final issue. Apart from it's strong support in England, it was not well read. But enough people had read it to find significant disagreement with its findings.
 Many physicians in europe and the US maintained that childbed fever could not be contagious, and that it was a separate disease from erysipelas and scarlet fever. In the US, the chief opposition came from two eminent physicians based at the Philadelphia medical school. Dr Hugh Hodges published a provocative article ,describing the "Non-contagiousness of puerperal fever", and was supported by his colleague, Charles Meigs.  They suggested that these cases were due to pure chance, or bad luck.  They did their utmost to suppress these findings. In fact, Charles Miegs took this evidence very personally,saying that "Doctors, are gentleman. and a gentleman's hands are clean".
On continental Europe, the situation was very much similar. Whilst the USA had Oliver Wendell Holmes to plead it's case, such voices in europe were largely absent. At least, until a physician based in vienna changed this.
Jakob Kolletschska was a professor of forensic pathology. As part of his work, he would routinely perform autopsies on cadavers. He would get his students to help him, pointing out details and abnormalities as they worked. It was during one of these exercises that one of the students accidentally cut him with an unlcean scalpel. The wound became septic, and he died as a result. He was no expert on childbed fever, but his death had a profund effect on his friend at that same institution, Ignaz Semmelweis.
  Ignaz Semmelweis had been appointed the head of obstetrics in the Vienna Lying-in hospital, and he was immediately appalled by the numbers of deaths from childbed fever at the hospital. Almost immediately, he set about trying to find a solution to this problem. Semmelweis noted that women who gave birth before reaching hospital tended to not to get this disease.
As the head of obstetrics, he was also aware that every morning, medical students and doctors would perform autopsies on women who had died the previous day. It was these sorts of dissections that Jakob Kolletchska performed on a regular basis, and it was on one of these were he had received his mortal wound.
In 1847,  disgusted with his inability to prevent these outbreaks, he took a holiday in Venice. It was while he was in Venice that he recieved word of the death of his friend. When he evenutally got around to reading the autopsy report, he was struck by how similar it was to those of the dead pregnant women whom he had dissected nearly every morning.
He realsied that if it was possible for his friend to have contracted a disease from a cadaver, then it was also possible that he, and his students could transfer this disease to the young mothers in their care. In that same year, he instituted new guidelines to the people workign under him: everyone should wash their hands before they start ont he wards, and before they examined patients.
The results were extraordinary. The numbers of patients contracting this disease fell from 18% to just 3%. But, just as his western counterparts, he faced strong opposition from the medical establishment.  Amongst his critics was the "Father of Modern Pathology" Rudolf Virchow, who exerted much influence amongst the medical establishment.
Semmelweis found himself passed over for promotions, and for work as a result of his strong views on handwashing. In the end, he returned to his native Hungary a bitter man. He was appointed to an unpaid position in St Rochus hospital, where he successfully enforced hygiene, and saved lives. He went on to obtain a professorship from the University of Pest and went on to publish his work in 1861, providing crucial statistical grounding to his theories . But he never forgot the insult he was dealt in Vienna.
Whilst some accepted his views, many did not, and they would often recieve a torrent of invective as a result. Semmelweis would publish open letters to his detractors, branding them as "Medical Neros" and "Murderers" in the popular press. He steadily became more unstable, until in 1864, he was committed to an Asylum. He died within weeks, tragically being felled by the very disease he had fought so hard against. But his work lived on afterwards, and his fervour in promoting hygiene was not forgotten.
Many would point to Semmelwies as the founder of hygienic practices in hospitals, but the story is more complex. In fact, the guidelines set out by Semmelweis had been discovered independently by a number of physicians in the west, who were mostly ignorant of each other's work. And the main reason for this was the strong opposition to these findings. The medical establishment didn't want to be told that they were killing their patients, or that their hands were dirty. Many doctors who had seen the effects of hygiene first hand, such as Francis Russell Elkington, implemented changes without telling anyone, and saw their patients improve. But people like Alexander Gordon, Robert Storr, Oliver Wendell Holmes and Ignaz Semmelweis fought hard to get their message out to the rest of the medical establishment. It was not enough for them to be better than their medical companions. We never heard them shrug and say "what's the harm" when they saw their fellow physicians blunder and kill their patients. They went out to change the world for the better, and they paid for it. Most of them ended their lives with their careers in ruin, and lives in tatters. But the lives they saved more than made up for it. They had reached enough people to provoke a groundswell of change. But it was slow and incremental. Whether we remember their names or not, there are people alive today who owe their existence to these men.
 Oliver Wendell Holmes was one of the few of them who managed to live long enough to see his work vindicated. Ten years before his death, he met the man whom he held responsible for that. He referred to as "one of the truest benefactors of his race". That man was Louis Pasteur.

References:
Internet:
 http://www.donny.co.uk/Doncaster/news/index.php3?ID=1175

Books:
The works of Oliver Wendell Holmes:  Medical Essays 1842-1882

Papers

Elkington F (1844). Observations on the Contagiousness of Puerperal Fever, and Its Connection with Erysipelas. Provincial medical & surgical journal, 7 (172), 287-8 PMID: 20793370

Storrs, R. (1842). History of a Puerperal Fever in Doncaster: Illustrated by Ten Cases, with Remarks BMJ, s1-4 (3), 45-51 DOI: 10.1136/bmj.s1-4.3.45

Dunn PM (1998). Dr Alexander Gordon (1752-99) and contagious puerperal fever. Archives of disease in childhood. Fetal and neonatal edition, 78 (3) PMID: 9713041

Storrs, R. (1843). Observations on Puerperal Fever: Containing a Series of Evidence Respecting Its Origin, Causes, and Mode of Propagation BMJ, s1-7 (166), 163-169 DOI: 10.1136/bmj.s1-7.166.163

De Costa CM (2002). "The contagiousness of childbed fever": a short history of puerperal sepsis and its treatment. The Medical journal of Australia, 177 (11-12), 668-71 PMID: 12463995

Adriaanse, A. (2000). Semmelweis: the combat against puerperal fever European Journal of Obstetrics & Gynecology and Reproductive Biology, 90 (2), 153-158 DOI: 10.1016/S0301-2115(00)00264-5

Dunn, P. (2005). Ignac Semmelweis (1818-1865) of Budapest and the prevention of puerperal fever Archives of Disease in Childhood - Fetal and Neonatal Edition, 90 (4) DOI: 10.1136/adc.2004.062901

Colebrook, L. (1956). The Story of Puerperal Fever--1800 to 1950 BMJ, 1 (4961), 247-252 DOI: 10.1136/bmj.1.4961.247