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: 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.

Antibiotics & Agriculture part 5: Stokstad's Genie

When  Robert Stokstad discovered antibiotic growth promoters, he was operating in industrial farming's nascent era. In the 1920's, farmers realised that with the right levels of vitamin supplements, they could raise chickens indoors safely cocooned from the outside environment. But this innovation came with some costs, as chicks born in this environment had poor survival, and didn't grow as fast as they did in the wild.
Stokstad's discovery of growth promoters was like a wish come true. Just by adding a low dose antibiotics, we could help more chicks survive into adulthood, and allow them to grow to full size whilst saving money feeding them. But, just like in any morality tale, wishes can come with consequences.
It turns out that the wholesale saturation of the industrial farming environment with antibiotics provided the perfect incubator for antibiotic resistance.

There have been a number of dangerous outbreaks of antibiotic resistant pathogens which can be traced directly to their usage in the agricultural industry. Salmonella, E.coli and even some strains of Staphylococcus aureus  have acquired resistance to antibiotics from farms.
Even more disturbing is that agricultural antibiotic usage has increased the numbers of resistance genes in the overall environment. These genes have been proven to transfer between different bacterial species. Even if the bacteria they reside in are themselves not a threat to human health, these genes can be transferred to pathogens that are threats.

The mounting evidence of this threat prompted some countries to act.
In 1984, after hearing reports that consumer confidence in meat safety was dropping, due to the antibiotic resistance threat, Swedish farmers requested a ban on all growth promoters. They were the first country to implement a ban, but they were not the last.
If you wanted to show the pitfalls of banning agricultural growth promoters, you can find no better example than that of the Netherlands. In these cases, the ban came into force before the farmers could improve infection control practices. As a result, they were beset by outbreaks of bacterial disease that required the use of more therapeutic antibiotics. In the Netherlands, this meant that there was no net change in the amount of antibiotics sold to the agricultural industry.
Sweden was not immune to this effect. Whilst the initial results of the ban showed promising reductions in antibiotic use, it was also characterised by increases in disease outbreaks on farms. The appetite for therapeutic antibiotics increased in direct response to these outbreaks, until it eventually rose to pre-ban levels.

When Denmark embarked on a similar plan to ban antibiotic growth promoters, they did so with an eye on the experiences of previous nations. With this system, they managed to reduce antibiotic use by around 90%. Somehow their ban managed to reduce infections without changing the welfare of their animals, and still managed to keep the Danish pig industry competitively priced.

So why did the Danish experience differ so much from the experiences of other nations ?

When they implemented the ban, they also ensured there was a comprehensive monitoring system in place to send out the alarm if new antibiotic resistant bacteria were produced, and a way of regulating the doses of therapeutic antibiotics given by veterinarians. They didn't ban all of their growth promoters at once. They first rolled back the use of avoparcin in 1995, then followed it with a ban on virginiamycin in 1998, and then finally a ban on all growth promoters in 2000. This gave the farmers the time to change the way they did farming to compensate for the loss of these growth promoters.

In preparation for the ban, Danish farms implemented basic infection controls. The routine disinfection of workers clothes, the workers themselves and their vehicles is now standard in many countries, to prevent the transfer of diseases between farms. Veterinary vigilance became watch words, with herds regularly inspected to ensure that outbreaks were caught and dealt with as early as possible.

The authorities also madee sure that every part of their system was committed to the reduction of antibiotic use. Veterinarians were prevented from directly selling antibiotics to farmers, they could only issue prescriptions, removing a potential conflict of interest. The numbers of antibiotic prescriptions given to specific herds was carefully monitored. Farms that were consuming high levels antibiotics could be spotted more easily under this system, and given the appropriate support.

Denmark also brought in new laws which changed the way that their pigs were raised and weaned. They recognised that a lot of their infection problems could be traced to their piglets being weaned too early and forced into an infection riddled world without the protective antibodies in their mother's milk, and immune systems not fully able to deal with the infection riddled world into which they were being exposed.

When Denmark put its ban in place, it did so with the knowledge that a massive full spectrum ban on antibiotic growth promoters could potentially harm its precious pork industry. When they drew up plans to ban antibiotic growth promoters, they paid attention to the science. They thought carefully about the consequences of the ban, and how they could best compensate for these effects using the best science available. Then they brought in the ban slowly, allowing farmers and veterinarians time to adapt to the new system, and ensured that the incentives presented by this new system were geared to limiting further usage of antibiotics.

In 2006, a broad ban on all antibiotic growth promoters was implemented across the European Union in response to mounting public pressure. Countries across the EU are now for better or for worse have to adapt their farming strategies to compensate for the loss of antibiotic growth promoters.
There are signs that the ban is working. The numbers of antibiotic resistance genes in the environment are decreasing.

But let's not pop the champagne corks just yet. There are a few problems with these bans that require further inspection.
In the initial stages of all the bans, outbreaks of bacterial disease often occur more frequently. In some scenarios, Veterinarians can be reticent in prescribing more antibiotics to treat these diseases, leaving the animals to suffer longer, and exposing them to greater risk of death. Improvements to infection control and animal husbandry only go so far in preventing outbreaks of disease. The situation in some countries is so bad that banning agricultural antibiotics actually increases the numbers of therapeutic antibiotics being used. The levels of antibiotics in some cases reaches the levels seen before the ban.
Every time an antibiotic is used, be it in animals, or in humans, has a chance of increase the numbers of resistant strains in the population. Taking this viewpoint, you may say that some of these bans have no effect at all. But you would be ignoring a crucial detail.
 In his Nobel prize speech, Fleming himself gave a warning about how mass underdosing could trigger the creation of antibiotic resistant strains, yet within ten years underdosing became standard practice within the agricultural industry.
It is crucial that we make sure that antibiotics are always used responsibly. The key reason why banning antibiotic growth promoters was that it was one demonstrable case in which antibiotics were used irresponsibly.

The other key problem with these bans is that no one knows the extent to which it will affect human health. It should prevent new strains of antibiotic resistant bacteria evolving on farms, such as livestock associated MRSA, or antibiotic resistant Enterococci.
However, expecting these bans to eliminate all antibiotic resistance is to unfairly place all of the blame on farming and agriculture for our current situation. The primary environment in which antibiotic resistant bacteria most commonly evolve, and where they are at their most dangerous, is found in hospitals. Any antibiotic resistance genes which have already made the jump into this environment are here to stay. Regulating antibiotic use in hospitals is difficult, because that is where we, as humans, need them the most. As much as we may worry about how the price of meat may be affected, if we cannot accept that relatively minor sacrifice, we will not be able to accept the changes and the costs needed to eradicate antibiotic resistance from our healthcare systems.

 The genie of antibiotic resistance is out of the bottle, but it wasn't just Robert Stokstad who had a hand in releasing it. We may sneer at growth promoters because they are the worst example of how we have squandered antibiotics. We may lament at how some faceless evil within the agri-business made the calculation that our future is worth trading for cheaper meat today. But we all had a hand in shaking the genie out of its bottle. We still have a hand in determining our own future. Even those of us who currently live in Europe may soon be inundated with american meat raised antibiotic growth promoters if certain trade agreements are successful. They will once again be faced with the same choice facing everyone else in the world, the choice between a full stomach today or better health tomorrow.

References

The WHO's internal evaluation on the termination of antimicrobial growth promoters in Denmark
http://www.who.int/gfn/en/Expertsreportgrowthpromoterdenmark.pdf

Danish Pig production in a European Context
http://www.lf.dk/~/media/lf/Aktuelt/Publikationer/Svinekod/LFEUBenchUK110318.ashx

Cogliani C., Goossens H. & Greko C. (2011). Restricting Antimicrobial Use in Food Animals: Lessons from Europe, Microbe, 6 (6) 274-279. DOI:

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

#MicroTwJC : The Creation of a Superbug

The year was 2004. The patient was a 6 month old baby girl. She was about to enter thoracic surgery, when the doctors found that she was harbouring methicillin resistant Staphylococcus aureus. Now, in most western hospitals, the origin of this bacterium would not be a mystery. But this was a hospital based in the Netherlands. The Dutch have a "search and destroy" mentality when it comes to dealing with superbugs, and have been very successful at keeping their hospitals free of MRSA. They wanted it to stay that way. They had to find the source of this MRSA, and put a stop to it. The hospital equipment was scrutinised for any traces of the bacterium. None could be found.
They eliminated the MRSA from the baby, and then sent her home with her parents. But when they followed up, the baby was once again colonised with MRSA. They went through the same process again and again, until they realised that the baby was continuously being re-infected with the bacterium from an unknown source. The doctors found that the babies parents were also carriers of MRSA. but where did they get the disease from ? If it wasn't coming from the hospital, then where was it coming from ?
It turned out that the family lived on a farm raising pigs. The pigs were tested. They were the source of the MRSA.
Other pigs on different farms in that area also carried this strain of MRSA. A number of other cases of farmers and vets catching MRSA off their pigs. They concluded that farmers were 760x more likely to get an MRSA infection than any other Dutch people. Further research revealed that 39% of pigs entering a slaughterhouse carried MRSA. Hospitals in close proximity to pig farms tended to see more patients with MRSA than hospitals that were far from pig farms. This MRSA appears to be different from the hospital associated MRSA's we are more familiar with. It is primarily carried by pigs, and was a leading cause of MRSA infection in the Netherlands.
 So now we know that pigs can carry MRSA, it is time to ask an important question. How did they get MRSA  ?  How did this particular strain evolve ? These are the questions that this weeks #MicroTwJC paper aims to answer.

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 Even Earlier Discovery of Antibiotic Resistance

So about a month ago, I wrote about how amazing it was that penicillin resistance was discovered as early as 1940, two years before it went on general sale. But whilst researching that article, I realised that Sulphonamide drugs entered the market long before penicillin, with their discoverer, Gerhard Domagk, being nominated for a Nobel prize in 1939. He had been tasked by Bayer pharmaceuticals to test out a gargantuan number of dye molecules to see whether they could kill off bacteria, and in the process , stumbled across the first antibiotic.
You may recall from the previous instalment that Heinrich Hoerlein was the man to recruit Gerhard Domagk into Bayer. Heinrich Hoerlein was a talented chemist, who had specialised in developing dyes for wool. How did this dye maker end up working to create one of the most important pharmaceuticals that the world had seen up until that point ? Why was it that when Bayer decided to devise new treatments against bacterial disease, they focussed on the compounds used to colour clothes ?

To understand how this state of affairs occurred, we need to go back further in time to the 1800s, and look at bacteria. If we were to do this in this era, we would need to get a good microscope. Bacteria tend not to be visible to the naked eye. So let us look down our microscope, what would we see ?
We would probably see tiny transparent blobs. This could mean that we either have lots of bacteria, or are looking at some air bubbles. There are various legends of scientists proclaiming that they have found an entirely new type of bacteria, only to later realise that this bacteria was nothing more than a bubble of air in the wrong place at the wrong time.
This is where dyes become important. The odds are that you are wearing clothes which have undergone the dye process. A dye works by chemically binding to the surface of whatever you want coloured.
A number of scientists of that era began to work on dyes that bind to cells, allowing them to be more easily seen under a microscope. This allowed scientists to see that bacteria came in all sorts of shapes and sizes, and that different species were associated with different diseases.
One of the pioneers of this research was a man named Paul Ehrlich. His PhD had been dedicated to studying how aniline dyes, which had previously only been used for fabrics, could actually be used to colour cells. He also noticed that dyes he used would colour some cells differently to others. Some cells would take up a lot of the dye, whilst others would not and remain transparent. At the age of 24, using the new "staining" techniques, he had managed to discover a new type of cell, known as a Mast cell.
A lot of his scientific achievements  could be tracked down to the one simple question he asked himself when he saw this effect: Why did some cells take up more dye than others?
He theorised that cells took up specific nutrients, and that receptors on the surface of these cells played a crucial role in this process. Different cell types have different receptors on their surface. some of these receptors allow dye molecules to enter the cell, and some do not. The reason that different cells "stained" differently was due to the different receptors on their surfaces.
He suggested that toxins on the surface of the bacteria bound the receptors on the surface of the host during infection. In response, the host cell would secrete these receptors to flood the toxins on the surface of the bacteria, thus neutralising them. He called these secreted receptors antibodies.
 Whilst this is far from our modern understanding of antibodies, it was a crucial step in the right direction, and he would be credited as one of the founders of immunology as a result of it.
He also suspected that bacteria also had receptors which they used to ingest dye molecules. He noted that some dyes were taken up by bacterial cells, but not human cells. He suggested that this was because the dye molecules resembled nutrients that the bacteria eat. If he could manufacture the chemical structures of these dye molecules to include poison, then he could have a chemical that kills of bacterial cells, and leave human cells alone. He termed these chemicals "Magic Bullets".
In 1904 came his first breakthrough, with a compound, known as Trypan Red, due to it's colour, and sucess for treating mice infected with trypanosomes. Whilst this was useful as a proof of concept, Trypan Red only worked against the types of trypanosomes that infect mice, but not those which attack humans
It was while he was working on this problem that researchers at the Liverpool School of Tropical Hygiene, Anton Breinl and Harold Wolferstan Thomas, discovered that a compound known as Atoxyl, though to be non-toxic for humans, could kill off trypanosomes. From 1906, a number of expeditions to Africa took it with them to protect themselves from the Sleeping Sickness caused by these organisms. Robert Koch, one of the founders of microbiology, used it to treat patients on the shore of Lake Victoria. It became incredibly popular at the time.
Intrigued, Paul Ehrlich investigated this wonder drug, in addition to the other dye based drugs he was developing. During the course of his research, he noticed a worrying trend. After prolonged therapy with these drugs, the resistance of the trypanosomes to these chemicals increased, until they were completely resistant to the therapy. He coined the term "fastness" to describe this trait in bacteria. The fact that he had observed this "fastness" occurring in response to such a broad range of chemicals suggested to him that this was an inevitable event.
Ehrlich was unexpectedly energised by this discovery of resistant organisms. This was because of the finding that once an organism became resistant compound, it was also resistant to chemicals with the same shape and structure. This provided evidence for his fledgling theory of surface receptors which bind to specific chemicals based on their shape and structure.
But his discovery of resistance put him on a crash course with Robert Koch, who had not observed this effect, and thus disputed that it had ever occurred outside of the lab. The main differences were that Robert Koch used much higher doses of Atoxyl than Ehrlich. Either way, Atoxyl was fast falling from popularity. Patients treated with it would go blind due to its severe side effects. A study in 1910 would show that it merely halted progression of trypanosome disease, and that patients were no better off using it.
 Ehrlichs lab was still screening drugs to fight off pathogens, and it came across compound 606, a derivative of atoxyl that not only had less severe side effects, but had proven utility against syphilis.
This was marketed as Salversan, and became an important drug in the fight against syphilis, and was used up until the 1940's, when penicillin replaced it.
The discovery of these drugs, and the apt demonstration that dye molecules could make good antibiotics cemented his place in history. One of his assistants, Wilhelm Roehl, would go on to head a research department at Bayer. It was he who would recruit a Dye chemist, Heinrich Hoerlein, to find the next big drug.
So whilst Ehrlichs theory of "magic bullets" would live on, and laid the foundations for the discoveries of Domagk and Fleming, what happened to his theories on antibiotic resistance ?
There were a number of weaknesses in Ehrlichs theories that a number of researchers called into question. Ehrlichs theories of antibiotics and antibiotic resistances were too simplistic. He posited that for each compound, there was a single path to resistance through the mutation of a single receptor. But we know that bacteria and other pathogens can adapt to antibiotics in multiple ways. This made it difficult to replicate his results, and even more difficult for him to explain why they didn't replicate.  The rules he had set out for explaining antibiotic resistance did not always hold true. The disparity observed between his experiments of Atoxyl, and of Kochs experiments did not help his case.
 This apparent wooliness would mask the threat of antibiotic resistance as a merely theoretical phenomenon. It would for the next 30 years be regarded as a curiosity that would never pose a threat to people.
Over a hundred years after Ehrlich's initial observation of antibiotic resistance, we have a slightly different perspective on his discovery than his contemporaries.

References

Gradmann C. (2011). Magic bullets and moving targets: antibiotic resistance and experimental chemotherapy, 1900-1940, Dynamis, 31 (2) 305-321. DOI: 10.4321/S0211-95362011000200003

Titford M. (2010). Paul Ehrlich: Histological Staining, Immunology, Chemotherapy, Laboratory Medicine, 41 (8) 497-498. DOI: 10.1309/LMHJS86N5ICBIBWM

Casanova J.M. (1992). Bacteria and their dyes: Hans Christian Joachim Gram, Historia de La Immunologia, 11 (4) DOI:

Ehrlich P. Address in Pathology, ON CHEMIOTHERAPY: Delivered before the Seventeenth International Congress of Medicine., British medical journal, PMID: 20766753

Kaufmann S.H.E. (2008). Immunology's foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff, Nature Immunology, 9 (7) 705-712. DOI: 10.1038/ni0708-705

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.

TMI Friday: A Vexacious Consequence of a Vasectomy

It was an emergency. The patient was 51 years of age, running a high fever, and pain and swelling in a particularly sensitive area, in which an operation had been performed a week previous. Gentlemen of delicate dispositions may wish to avoid reading further, for that operation was a vasectomy.

The purpose of a vasectomy is contraception, to make sure that a man cannot impregnate a woman with his sperm. A vasectomy works through preventing sperm from escaping from your testicles, where they are manufactured. It does this by cutting the vas deferens, the tube through which the sperm travel out of the testicles. This procedure has become relatively advanced in recent years.

The gentleman in question had a "No scalpel" incision vasectomy. This has a number of benefits , not least that it doesn't involve a scalpel being wielded near to a "gentleman's dangling region". It its quicker, leaves a tiny operation scar, which means less bleeding pain and infection, and more importantly, a quicker return to sexual activity. 

The 51 year old gentleman however had clearly acquired some form of infection after the operation. Infection after a vasectomy is generally uncommon. They then found the identity of the bacterium causing this infection. It was Streptococcus pyogenes, the bacterium that commonly causes sore throats. Long time readers of this blog probably have some idea of where this is going...

His wife had been looking after their children who were suffering from sore throats. And unbeknownst to anyone, the Streptococcus pyogenes had been passed to her, and was settling on her tonsils. The night before the fateful emergency visit, she and her husband had an intimate moment. During this process, the bacteria on the wife's tonsils somehow ended up on the husbands genitals. The paper describing this clinical case describes the infectious process that followed:

It is reasonable to assume that the vasectomy incision was only superficially healed, and therefore, violated and impregnated during the “trauma” of oral intercourse.

This is one of those cases where a series of events coincide, which results in a bizarre disease complication.

That was my TMI Friday, I hope you endured it as well as I did.

Ramaswamy K. &; Kaminetsky J. (2011). Unique Infective Complication after Routine Vasectomy: A Case Report, The Journal of Sexual Medicine, 8 (9) 2655-2658. DOI: 10.1111/j.1743-6109.2011.02345.x

TMI Friday: Taking a Bite out of Love

Love isn't commonly encountered within the medical literature. The romantic lives of two people in love is a subject that rarely requires the attention of a doctor.

But occasionally in the violent throes of a passionate embrace, there is an emphasis on the violence. With this in mind, let us consider the Hickey.

Once when I was in school, I met up with my friend and the first thing I said to him was "What the f**k happened to your neck ? Did you get attacked ?" at which point I realised the girl next to him started to giggle.
I later learned that during the violent throes of passion, that occasional nibble may occur, leaving a bruise, or just a red mark. But on occasion, some couples go a little bit too far. This is where medical professionals get involved.
In a set of case reports published by the British Journal of Surgery in 1990, 7 cases of what are described as "Traumatic" love bites are reported. I shall summarise them below

1. Patient 1, a 35 year old man, came into hospital complaining of a hard lump in his shoulder that had been bothering him for long time. It was a worrying lump, and the doctors initially suggested that it was some sort of cyst. When they removed the cyst, they were dismayed to find... a plastic tooth. It turned out that he had engaged in intimate relations with a lady who was not only dressed as a vampire, but possessed an incredible commitment to the lifestyle.
2. Patient 2 arrived at the hospital with an abscess in his neck that was swollen with bacteria, caused by a particularly violent love bite that had happened 3 weeks previously
3. Patient 3 arrived at the emergency room, bleeding from the jugular vein that was caused by deep bite marks that had been inflicted 2 hours earlier under undisclosed circumstances.
4. Patient 4, a 26 year old woman had been suffering from cellulitis in the neck for about 3 days before she went to hospital, and later confessed it was due to "ferocious love biting" by her boyfriend, and in response, the surgeons gave her a course of antibiotics and also a tetanus shot.
5. Patient 5 appeared to accept some form of responsibility for the infected wound on his neck, as the wounds were inflicted after he had returned from a long holiday by his "frustrated" girlfriend.
6. I feel sorry for Patient 6, who had to cut off her honeymoon early after her drunken husband accidentally bit off her left nipple. The doctors don't mention the fate of this relationship, but I would be very surprised if "Divorce" was not a key feature of it.
7. Patient 7 suggested that the primary reason for the infected injury in the left breast was due to the short stature of her paramour.

Only in two of these cases is the injury in itself severe enough to merit an immediate visit to hospital. The majority of the problems caused by these human bites come from infection. The human mouth is generally full to the brim with bacteria, that could potentially become hazardous if introduced into a wound.

When one attempts a lovebite, always remember to take a sensible nibble, if you end up with a mouthful of blood then you are probably doing it wrong. Unless you are a vampire, in which case, check that you still have all of your teeth at the end of it.

Al Fallouji M. (1990). Traumatic love bites, British Journal of Surgery, 77 (1) 100-101. DOI: 10.1002/bjs.1800770134