lecture 12 A brief history of antimicrobial chemotherapy

Question 1

Overview of lecture:

Answer 1

1. Understanding Early Treatments Against Infectious Disease
   Early treatments for infectious diseases largely relied on natural remedies, traditional medicines, and practices based on observations rather than scientific evidence. Some of the earliest treatments included:

Herbal remedies: Plants and herbs with natural antimicrobial properties.
Bloodletting and leeches: Aimed at removing “bad blood” believed to cause disease.
Sulfonamides (pre-antibiotic era): The first class of drugs to be used against bacterial infections before the discovery of antibiotics like penicillin.
The discovery of antibiotics in the early 20th century revolutionized the treatment of bacterial infections, leading to a decline in mortality rates from infectious diseases.

2. Define “Selective Toxicity”
   Selective toxicity refers to the ability of an antimicrobial drug to target pathogens (such as bacteria, fungi, or viruses) without causing damage to the host’s cells. It is a fundamental concept in antimicrobial therapy, as it ensures that the drug is lethal to the pathogen but minimally harmful to the host organism.
3. Different Broad Categories of Antimicrobials
   Antimicrobials can be classified into several broad categories based on the type of microorganisms they target:

Antibiotics: Used to treat bacterial infections (e.g., penicillin, tetracycline).
Antifungals: Used to treat fungal infections (e.g., fluconazole, amphotericin B).
Antivirals: Target viral infections (e.g., acyclovir, oseltamivir).
Antiparasitics: Treat infections caused by parasites (e.g., chloroquine for malaria, metronidazole for Giardia).

4. Phenotypic Methods for Determining Antibiotic Susceptibility In Vitro
   Phenotypic methods involve testing the actual growth of bacteria in the presence of antibiotics to determine their susceptibility. Common methods include:

Disk diffusion test (Kirby-Bauer test): Measures the zone of inhibition around an antibiotic disk placed on a bacterial culture.
Minimum inhibitory concentration (MIC) testing: Determines the lowest concentration of an antibiotic that inhibits visible growth of the microorganism.
E-test: A gradient method that combines both the principles of the disk diffusion test and MIC.

5. Recent and Predicted Trends in Antimicrobial Consumption and the Impact of Resistance
   Increased consumption: There has been a significant rise in the global use of antibiotics, especially in low- and middle-income countries, driven by increased access and overuse in both humans and animals.
   Antimicrobial resistance (AMR): The excessive use of antibiotics has led to the development of resistant strains of bacteria (e.g., MRSA, multi-drug-resistant TB), making it harder to treat common infections.
   Predicted trends: It is expected that antimicrobial resistance will continue to rise if current consumption patterns persist, leading to a potential crisis in treating infectious diseases in the future.
6. Treatment Plans for a Range of Bacterial Infections
   Treatment plans vary depending on the type of bacterial infection and its s everity. Some common examples include:

Streptococcal pharyngitis (strep throat): Treated with penicillin or amoxicillin as first-line antibiotics.
Urinary tract infections (UTIs): Typically treated with nitrofurantoin or trimethoprim-sulfamethoxazole.
Community-acquired pneumonia (CAP): Empiric treatment often includes macrolides (like azithromycin) or doxycycline for mild cases.
Methicillin-resistant Staphylococcus aureus (MRSA): Treated with vancomycin or linezolid in more severe infections.

Understanding these topics helps in making informed decisions about the use of antimicrobial agents and addressing the growing concern of resistance.

Question 2

Early treatment for infections

Answer 2

when we refer to antibiotics we refer to things that affect the bacterias cells not just something that kills and affects just masses of tissue, that why we don’t refer to things like mercury that will just kill all the cells including healthy normal host cells as antibiotics, that is not a way of controlling an infection it is just a way to excise disease tissue

Question 3

Different categories of antimicrobial:

Answer 3

Question 4

Biocides: disinfectants and antiseptics

Answer 4

we would call these broad spectrum as they have no finesse, they do not target just one cell but just kill everything and denature or kill whatever

when it comes to things like IMS or rubbing alcohol the antibiotic affect is that it evaporates of the skin and dehydrates whatever is there; it can dehydrate bacterial outer membranes

triclosan is an banned in many countries because it does not biodegrade, it is a very stable antimicrobial product that does not biodegrade and when it is used in plastics or liquids it can remain in water sources and remain without degrading; it can be thrown in the environment and then put a selective pressure on environmental microbes

Question 5

Principles of selective toxicity

Answer 5

the targets of antibiotics are to be very specific and primarily to act upon targets unique to bacteria although they can still sometimes harm eukaryotic cells but they’re primarily produced to take down bacteria specific targets

they have a selective toxicity- the drug has a particular process in a bacterial cell that it upsets without it upsetting the same or equivalent process in a human cell. i.e it attacks the bacteria cell wall not the eukaryotic membrane
- there can be side effects but the patient should recover

-an antibiotic is something that can kill a broad range of microbes

gram staining observations are where the idea of selective toxicity came from

antibacterials have 2 broad mechanisms of action, they can either kill the cells or they can inhibit their growth

Q2- bacteriostatic antibiotics can stop the growth of antibiotics and let the immune system kill of the remaining ones
- or the bacteriostatic antibiotics can stop the growth of antibiotics and the cells will eventually die from age as they don’t live forever and can no longer divide, multiplying or growing

Question 6

The discovery of clinically useful antibiotics

Answer 6

penicillin is the first antibiotic, it has applications amongst many different species

Question 7

The discovery of clinically useful antibiotics

Answer 7

Question 8

Q3. What does “serendipitous discovery”
mean?

Answer 8

penicillium mould does not get infected by bacteria but it does compete with bacteria for space and nutrients, so fungi that exude small amounts of antibiotic that will help their survival when they’re growing in mixed environments and communities of microbes
when this principle was discovered it began a hunt for the next useful drug

Q3
this was not a serendipitous discovery because it was systematic, this was not an accident like the discovery for penicillin
- systematic means they were actually looking for something

Question 9

Summary of mechanisms of action

Answer 9

Q4
selective toxicity is important, cell walls are used because eukaryotes do not have cell walls and bacteria do have cell walls whilst nucleic acid synthesis and replication are highly conserved processes between all groups of cells including eukaryotes and prokaryotes but only about 18 enzymes that are different in terms of nucleic acid synthesis compared to entire structure in the form of the cell wall of prokaryotes and membrane of human eukaryotic cells, there is no equivalent structure in terms of cell walls to attack in our eukaryotic cells

Q5
you can have probiotics that reduce harm to the normal bacterial flora of their body; infections can arise when your normal flora are disrupted and pathogens can take hold so keeping normal flora healthy can reduce the risk of infection

Question 10

Summary of mechanisms of action
Q6. Based on the diagram on the previous slide, identify which antibiotic
class corresponds to the following target sites

Answer 10

-Topoisomerase
-involved in DNA replication so Topoisomerase activity is affected by nucleic acid synthesis so antibiotics such a Quinolones

-Peptide bridge
important in the cell wall of bacteria so antibiotics such as beta-lactams

-Translocation
protein synthesis antibiotics
such as linezolid

-Transpeptidation
protein synthesis antibiotics
such as linezolid

-60S ribosome subunit
proteins synthesis antibiotics
such as linezolid

-Folic acid synthesis enzymes
related to anti-metabolite antibiotics such as sulphonamides

Question 11

Summary of mechanisms of action

Which antibiotic corresponds
to which process below?

Answer 11

-Topoisomerase
-involved in DNA replication so Topoisomerase activity is affected by nucleic acid synthesis so antibiotics such a Quinolones

-Peptide bridge
important in the cell wall of bacteria so antibiotics such as beta-lactams

-Translocation
protein synthesis antibiotics
such as linezolid

-Transpeptidation
protein synthesis antibiotics
such as linezolid

-60S ribosome subunit
proteins synthesis antibiotics
such as linezolid

-Folic acid synthesis enzymes
related to anti-metabolite antibiotics such as sulphonamides

Question 12

Summary of mechanisms of action

Q7. What does antibiotic resistance actually mean?

Q8. Identify an infectious disease (or related group of diseases),
where you think resistance has risen disproportionately in recent
years. Briefly explain your rationale.

Q9. Follow-up question: there was a controversial omission on this list that has now
been included – can you guess what it is?

Answer 12

Q7. What does antibiotic resistance actually mean?
-antibiotic resistance means whether or not the bacteria can survive the concentration that would be achieved in the serum of the patient who is being treated with that antibiotic
- so it means at a therapeutic dose the microbes are still able to grow and survive. And can grow at doses equivalent to those that would normally be expected in a clinical scenario to kill off or treat the infection

Antibiotic resistance refers to the ability of bacteria to survive and multiply despite the presence of antibiotics that would normally inhibit their growth or kill them. When bacteria become resistant, standard treatments become less effective or completely ineffective, making infections harder to treat and increasing the risk of disease spread, severe illness, and death. Resistance occurs naturally over time, but the misuse and overuse of antibiotics in medicine and agriculture have accelerated this process.

Q8. Identify an infectious disease (or related group of diseases) where resistance has risen disproportionately in recent years.

One infectious disease where resistance has risen disproportionately in recent years is tuberculosis (TB), specifically multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB).

Rationale:

MDR-TB is resistant to at least isoniazid and rifampicin, the two most powerful first-line TB drugs.
XDR-TB is even more severe, being resistant to first-line drugs and at least one second-line drug.
The rise in resistant TB strains is primarily due to inadequate treatment practices, including incomplete courses of medication, incorrect prescriptions, and poor-quality drugs. The spread of resistant strains is particularly challenging in regions with limited healthcare resources.

Q9. Follow-up question: there was a controversial omission on this list that has now been included – can you guess what it is?
The controversial omission that has been included in the context of antibiotic resistance is Neisseria gonorrhoeae, the bacterium responsible for gonorrhea.

Explanation:
MRSA is one
Gonorrhea has developed resistance to nearly all antibiotics that were once effective against it, including penicillin, tetracycline, and fluoroquinolones.
It has become a significant public health concern due to its ability to rapidly develop resistance to new treatments, leading to a situation where very few effective antibiotics remain, such as ceftriaxone.
The inclusion of Neisseria gonorrhoeae on priority pathogen lists by the World Health Organization (WHO) and other health authorities highlights its growing threat as a drug-resistant infection.

An infectious disease where resistance has risen disproportionately in recent years is Neisseria gonorrhoeae, the bacterium responsible for gonorrhea.

Rationale:
Neisseria gonorrhoeae has developed resistance to almost all classes of antibiotics traditionally used to treat it, including penicillins, tetracyclines, macrolides, and fluoroquinolones.
More recently, there has been a significant rise in resistance to third-generation cephalosporins (like ceftriaxone), which are the last line of effective treatment options.
The rapid development of resistance in Neisseria gonorrhoeae is alarming because it leaves very limited options for treatment, raising concerns about the possibility of untreatable gonorrhea infections in the near future.
This rapid rise in resistance has led to the bacterium being classified as a high-priority pathogen for new antibiotic research and development, highlighting the urgent need for new therapeutic options to control its spread.

Question 13

Q9. Identify an infectious disease (or related group of diseases), where you think
resistance has risen disproportionately in recent years. Briefly explain your rationale

Answer 13

The infectious disease that was controversially omitted but has since been included on this list of priority pathogens is Mycobacterium tuberculosis (the bacterium that causes tuberculosis or TB).

Explanation:
Mycobacterium tuberculosis was initially left off the WHO priority list for antibiotic-resistant bacteria because it was considered to be a separate category, given the unique nature of TB control programs and its long history of specific drug treatments.
However, due to the rise of multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB), it has become increasingly clear that TB represents a critical public health threat and fits the criteria for a priority pathogen.
The growing resistance to first-line and second-line anti-TB drugs has made it much harder to treat and control TB, necessitating its inclusion on the list to ensure focused research and development of new treatments.
The decision to include TB in discussions of antimicrobial resistance reflects its significant impact on global health and the urgent need for new antibiotics and better treatment strategies.

Question 14

The rise and fall of MRSA

Answer 14

there has been a decrease in MRSA infections as techniques to control and limit spread beyond having antibiotics have improved so methods are available to limit spread of disease beyond just having new drugs

Question 15

Epidemiological trends in ESBL infection

Answer 15

rates of serious infections has massively increased amongst these very resistant bacteria

Question 16

Introduction of antimicrobial agent

Answer 16

top layer shows when antibiotics were developed and bottom layer shows when resistance was developed
-alot of drugs have only a short lifespan before antibiotic resistance develops

Question 17

Q10. The newest drug, bedaquiline, is used for which microbes / disease?

Answer 17

The newest drug, bedaquiline, is used to treat tuberculosis (TB), specifically multidrug-resistant tuberculosis (MDR-TB).

bedaquiline is a novel drug used to treat TB, this is just used for TB

Key Points:
Bedaquiline is an antibiotic that targets the mycobacterium responsible for TB, Mycobacterium tuberculosis.
It is used as part of a combination therapy for MDR-TB, where the bacteria are resistant to at least isoniazid and rifampicin, the two most powerful first-line anti-TB drugs.
Bedaquiline works by inhibiting the ATP synthase enzyme in the bacteria, which is essential for their energy production and survival.
Its introduction has been a significant advancement in the treatment of MDR-TB, providing a new option for patients with drug-resistant strains of tuberculosis.

Question 18

Cell walls of Gram-positive &
Gram-negative bacteria

Answer 18

we have selective toxicity because mamalian cells do not have cell walls so we can target structures and processes in cell wall synthesis that would not occur in our own cells

gram positive and gram negative bacteria both have cell walls but it is much more pronounced in gram positives they also all have peptidoglycan however it can be harder for antibiotics to be developed against gram negatives as they have a thinner layer of peptidoglycan but also a thicker layer of peptidoglycan which can make it harder for antibiotics to reach the active sites

mycoplasmas are a unique type of bacteria that do not have a cell wall

Question 19

Inhibitors of cell wall synthesis (this is a class/category of antibiotics)

Answer 19

3-D structure of the peptidoglycan in bacteria peptide bridges join the NAM molecules

Question 20

Cell wall synthesis with site of action of antibiotics

Answer 20

these are the 5 main groups of antibiotics which can target the different stages of cell wall synthesis- these are selectively toxic
-beta-lactams and glycopeptides are the 2 most commonly used classes of antibiotics
penicillin is a type of beta-lactam

the -beta-lactams and glycopeptides affect the construction of the peptide bridges in the peptidoglycan cell walls - they stop the chains of nag and nam from attaching to each other

Question 21

Mechanism of action of glycopeptides

Answer 21

TP links the pentapeptide chains together between the peptidoglycan chains

autolysins exist to break down old cell wall in order to build the new cell wall chains so they continue to break down old cell wall whilst the new molecules cannot bind together and build a new chain layer so larger sections of the cell wall split over time and the cell ends up rupturing and breaking apart as structural integrity is lost

Question 22

Inhibitors of peptidoglycan synthesis

Answer 22

vancomycin the important drug to remember

when new drugs that come in to replace old drugs that bacteria have become resistant too Some of these new variants of antibiotics don’t have any difference in terms of how they broadly interact with bacteria, but differ in terms of being more stable, in their side effects, the dosing regime will be different and more manageable depending on the condition of the person that needs it, teicoplanin is given to young babies because it is more manageable for them

vancomycin is a drug of last resort for MRSA as it can be toxic and needs to be carefully managed

bacteria can develop resistance by changing the structure of the specific part of the cell that is targeted and bonded to by the antibiotics such as the cell wall peptide bridging molecule so that the vancomycin can no longer bind

Question 23

Mechanism of action of Beta-lactam antibiotics

Answer 23

the beta-lactam mimic the part of the structure that would normally be fed into the growing cell wall, these antibiotic classes have a specific beta-lactam ring, this is the active part of the molecule and this will feed and link into the growing cell wall so you will not get your cross linked nam-nag strands because the penicillin molecules become bound in place of the bacterial particle that would normally go into the structure

Question 24

Different classes of ß-lactams

Q11. What would you
hypothesise is/are the
function(s) of these side
chain variations?

Answer 24

the side chains that create slightly different versions of beta lactam antibiotics, they’re really there to maybe make the molecule more stable against bacterial resistance enzymes. Or it could be so that they’re less toxic to the host, or so that the dosing regimes, are a bit easier to the host so they don’t need 4 or 5 doses every day, but maybe just one instead. So that’s where you see loads of different versions of penicillin and beta lactam and other antibiotics

Question 25

Mechanism of action of beta-lactamase enzyme

Answer 25

the majority of resistance that occurs from because of beta-lactamase not working occurs because the beta-lactamase enzyme breaking down the beta lactam structure so the active part of the molecule becomes disintegrated and so the antibiotic will no longer be able to bind to the structure it needs to bind too and the bacteria cell wall will remain normal however the resistance that is caused in MRSA is because the bacteria change their target site

Question 26

ESBLs * What are ESBLs?

Answer 26

extended spectrum means the molecules will be more stable to bacterial resistance however what happens is more advanced enzymes end up developing to break down these beta lactam antibiotics ESBLs are a huge variety of antibiotics to help deal with the evolution of bacteria and so it is an arms race between bacteria and antibiotic development, we develop new drugs and bacteria evolve to develop new more advanced enzymes to break down the antibiotics the green box contains the bacteria that are developing lots of resistance because they have beta-lactamase enzymes

Question 27

Beta-lactamase inhibitors Q12. Why does the clavulanic acid component of coamoxiclav have to have the properties described in the bullet point list?

Answer 27

these are modifications to antibiotics that can help to keep beta lactamase enzymes in check. one of these approaches is, , where you administer a beta lactam inhibitory drug, alongside your main beta lactam antibiotic. so say you've got, your main antibiotic, which is amoxicillin, And this is a type of penicillin that's been developed to be a bit more active against gram negatives and a bit more stable against bacterial enzymes. And you bind it with it, something called clavulanic acid And you can see that both the amoxicillin And the clavulanic acid have this beta lactam ring now, clavulanic acid is also a beta lactam antibiotic but is not very active on its own, But now when you add it to amoxicillin, then you suddenly have two beta lactam molecules that you're administering in the same drug. so to answer question 12 you've got your beta lactamase inhibitor that has a very high affinity for the enzymes that the bacteria are producing to break the antibiotic down. then the clavulanic acid acts as a magnet for the beta lactamase enzymes as the bacteria are producing enzymes to break the antibiotic down, thus the beta lactamase will be mopped up and irreversibly bound to the clavulanic acid because of its high affinity to the enzyme. meanwhile the amoxicillin is free to inhibit the the cell wall construction of the bacterium

Question 28

B-lactamase inhibitors

Answer 28

Question 29

Difference between beta-lactams and vancomycin

Answer 29

the bacterial beta-lacamase inhibitor will be bound to the inhibitor component of the antibiotic whilst the active drug component will be free to breakdown the cell wall of the bacteria the difference between vancomycin and beta lactams are that the vancomycin binds to those sticky ends when those peptide bridges are being formed and the beta lactamase, they bind to the transpeptidase enzyme by sort of competitive inhibition by fitting in where the peptide enzyme would normally link those strands together, the overall effect in both cases is that the cell wall falls apart and the cytoplasm will spill out

Question 30

Penicillin resistance is widespread but can still be used to treat several important infections: Q13. What bacterial genus is most commonly associate with endocarditis?

Answer 30

bacterial infections can still be used with penicillin- it is important that we use penicillin where we can is because you should use antibiotics where there is still some use so that you do not draw on some antibiotics where resistance is already becoming even more of a problem- so you should use it as much as you can so you do not put pressure on other drugs where resistance is not yet pronounced Q13- streptococci Pseudomonas aeruginosa is a bacteria that is a very resistant bacteria on our list of clinical pathogens and you have very specialist antibiotics of the beta-lactam group that are used against this bacterium, They're very, very highly stable antibiotics among the dozens of beta-lactamase enzymes that Pseudomonas can throw out

Question 31

Spectrum of activity of antibiotics (from Brock Biology of Microorganisms) Q14 – why are there fewer antibiotics available for obligately parasitic bacteria?

Answer 31

Q14-  You've got much more of a barrier to actually get into the host cell and then into the bacterial cell. And if you've got gram negative bacteria then you've got the extra challenge that you also have an intracellular bacteria. and You've got to get the antibiotic through the host cell, through the outer membrane of the gram negative, and then into the active part of the cytoplasm or wherever the drug is having its effect Obligate parasitic bacteria are a group of bacterial pathogens that can only reproduce by invading a eukaryotic host cell

Question 32

inhibitors of cell membrane function and synthesis Mechanism of action of polymyxins:

Answer 32

there are fewer antibiotics in this group  because our cell membranes are more similar here where we don't have a cell wall and We do have a cell membrane. So we share this structure obviously with bacteria. And there are significant differences in some of the structural elements that mean that we can develop drugs that affect one type of cell and not the other. but there aren't that many available, one of the main groups available are the polymyxins (also called colistin) and these affect the charges in the cell membrane components and that disrupts the organisation of the cell membrane and the cell membrane breaks apart and the cytoplasm will begin to leach out so you get inner and outer cell membrane lysis that is affected by the polymyxin group and this particular group of antibiotics only acts on gram negatives so does not get into gram positives very easily

Question 33

Colistin metabolism in person with renal function disorder:

Answer 33

colistin has usually been administered by IV problem with colistin is that it can cause unpredictable side effects; it is administered via an inactive form (colistimethane) and is converted into its active form in the bloodstream but a lot of the drug when it is first administered doesn't actually get converted in the bloodstream because it's passed very quickly out of the body through the kidneys. So renal clearance, actually diverts most of the colistimethane out of the body, So for quite a high dose of drug actually only quite a small amount ends up being activated inside the body because most of it is excreted through the urine the reason there were lots of adverse serious side effects that couldn't be predicted was because it was very difficult to work out how to adjust the dose, or how the drug was acting in people who may have poor renal clearance. that doesn't mean someone who has one specific disease but anyone who has slightly misfunctioning kidneys then colistin isn't passed out of the body through the urine And that means you have much more drug that gets activated to the active form of colistin in the bloodstream and you can basically get overdoses forming from the same dose that different patients would take as Anyone with some type of kidney damage could get many more different severe side effects if they're not excreting the drug and if it is all getting converted in the blood stream because it was very difficult to adjust dosing regimes to account for kidney damage for this particular drug in the 1960s they may not have cared for it as they had so many other antibiotics

Question 34

Example dosing chart showing colistin dose adjustment for patients with impaired creatin clearance rates. Schellack et al. 2016

Answer 34

because it was very difficult to adjust dosing regimes to account for kidney damage for this particular drug in the 1960s they may not have cared for it as they had so many other antibiotics so left the drug for other things But now we have, particularly through analysis of things like HPLC, molecular analysis, we have a much better understanding of how the drug, is processed by people who have various types of kidney disorder. And it means that we now have much more robust dosing regimes so that we don't cause overdose essentially in people with renal damage. using the screenshot you can see that if renal impairment is categorised at various levels of severity according to creatinine clearance, then somebody whose creatinine clearance is known and their kidney health is known can receive slightly different doses of drugs of colistin, so the dose decreases as kidney function also decreases. we've had to do this because we've run out of drugs since the 1960s and we've got more resistance to gram negatives which colistin affects then this drug becomes more important because we've resistance to everything else

Question 35

Impact of colistin resistance Q15. Antibiotic resistance is driven by selective pressure – if patients were not being prescribed the drug, where was all the resistance coming from?

Answer 35

Survey of isolates from pork meat sold in China – studies found up to 20% of meat samples contained resistant bacteria Q15- resistance was coming from using the drug in animal husbandry and farming, it was used as a growth promoter, Growth promoters are substances given to farm animals to improve their growth rate, feed efficiency, and protein conversion- The idea being that if, uh, you're feeding animals for meat products and they are putting a lot of their energy and their food into keeping all of their microbiota alive, If you administer them antibiotics, then it kills off their microbiota and more of the food you're giving them goes into producing flesh, which is obviously consumed as meat. It's also able to control epidemics of bacterial infection among large, intensively herded flocks of animals. intensive farming methods use a lot of different antibiotics with colistin being one of them so what that means is people have been exposed to colistin if they eat meat that has been produced this way and their gut flora, their E.coli, their Klebsiella and other bacteria have been exposed to low levels of colistin, even though no one's been treated with it clinically because it's been in the food chain. So now when those same commensal organisms cause you a septicaemia or a post-operative infection The colistin that we've now revived is no longer as useful as it could have been because it's been misused for all of those decades, and so many bacteria have been exposed to it. So this is a disaster because some of the newer drugs that have been developed have all mostly been developed against gram positives. So we still have an emergency situation in needing antibiotics to deal with gram negatives and one of the things we could have done, in terms of revitalising colistin, has been compromised because of its use in the agricultural industry.

Question 36

Spectrum of activity of antibiotics (from Brock Biology of Microorganisms)

Answer 36

We have more antibiotics against the gram positives than the gram negatives. We still have quite a lot against the gram negatives, but we have a lot of resistance forming here. and thus the polymyxins group are very important as reserves of antibiotics to treat some of these gram-negative bacterial infections 

Question 37

Q16. A cystic fibrosis patient is prescribed nebulised polymyxin in combination with piperacillin prescribed intravenously? What possible explanation may there be for this course of action?

Answer 37

Pseudomonas aeruginosa is what we would be looking to treat, a cystic fibrosis it is likely the person has a respiratory infection. polymyxin is a cell membrane disruptor, piperacillin is a very advanced beta lactam antibiotic What we are hoping to achieve by having these two antibiotics administered in these two different ways is because cyctic fibrosis Pseudomonas infections in the lung. they're inhaled, they grow inside the lung, they are very resistant to antibiotics Pseudomonas also forms biofilms which can make them very resistant to antibiotics So if you're having antibiotics administered intravenously and nebuliser inhaled, then you're actually attacking that infection from both directions, The side of the bacterial biofilm, essentially that's growing next to the lung and in the lung tissue that's affected by the antibiotic circulating systemically through the bloodstream. And you're also attacking it by inhaling it so that anything that's growing on the lung surface is getting a second dose of antibiotics directly to the external surface. So it brings home a point here that usually you don't administer more than one drug at a time. It used to be very common. But in order to preserve antibiotics, now only one type of drug is usually given at a time, but there are exceptions where you've got very severe or recalcitrant infections, such as cystic fibrosis, lung infections. So you have inhaled antibiotic and intravenous antibiotic two different classes and you have much more chance of successfully eliminating the infection than just trying one approach alone. for a cystic fibrosis patient, the combination of nebulized polymyxin (such as colistin or polymyxin B) and intravenous piperacillin could be prescribed to treat a Pseudomonas aeruginosa infection, which is common in these patients. Here’s a possible explanation for this treatment strategy: Explanation: Targeting Pseudomonas aeruginosa: Cystic fibrosis (CF) patients frequently develop chronic lung infections with Pseudomonas aeruginosa. This bacterium is difficult to eradicate due to its resistance mechanisms and its ability to form biofilms in the lungs of CF patients. Dual-Route Therapy (Nebulized and Intravenous): Nebulized polymyxin: Delivering polymyxin directly to the lungs via a nebulizer allows for higher local concentrations of the drug at the infection site with reduced systemic toxicity. This approach can be particularly effective against bacteria residing in the airways and biofilms. Intravenous piperacillin: Administering piperacillin intravenously ensures that the antibiotic reaches the bloodstream and can treat any systemic spread of the infection. Piperacillin is a broad-spectrum beta-lactam antibiotic that is also effective against Pseudomonas aeruginosa. Synergistic Effect: The combination of polymyxin (which disrupts the bacterial cell membrane) and piperacillin (which inhibits cell wall synthesis) can have a synergistic effect, enhancing the overall efficacy against multidrug-resistant strains of Pseudomonas aeruginosa. Preventing Resistance Development: Using multiple antibiotics with different mechanisms of action reduces the risk of the bacteria developing resistance, which is particularly important in treating chronic infections in cystic fibrosis patients. This combination therapy approach aims to maximize bacterial eradication, minimize resistance development, and effectively manage the severe respiratory infections commonly seen in CF patients.

Question 38

Q1. Triclosan has been banned in some countries – from the information below, why might this be? Q2. How do bacteriostatic antibiotics treat infection, given that they do not kill bacterial cells? Q3. What does “serendipitous discovery” mean? Q4. Why are there so many antibiotics that act on the cell wall, and so few that act on nucleic acids? Q5. Can you think of how infection can be managed by addressing stages 1 and 2 of the infection process? Q6. Based on the diagram on the previous slide, identify which antibiotic class corresponds to the following target sites * Topoisomerase * Peptide bridge * Translocation * Transpeptidation * 60S ribosome subunit * Folic acid synthesis enzymes Q7. What does antibiotic resistance actually mean? Q8. Identify an infectious disease (or related group of diseases), where you think resistance has risen disproportionately in recent years. Briefly explain your rationale. Q9. Follow-up question: there was a controversial omission on this list that has now been included – can you guess what it is? Q10. The newest drug, bedaquiline, is used for which microbes / disease? Q11. What would you hypothesise is/are the function(s) of these side chain variations? Q12. Why does the clavulanic acid component of co-amoxiclav have to have the properties described in the bullet point list? Q13. What bacterial genus is most commonly associate with endocarditis? Q14 – why are there fewer antibiotics available for obligately parasitic bacteria? Q15. Antibiotic resistance is driven by selective pressure – if patients were not being prescribed the drug, where was all the resistance coming from? Q16. A cystic fibrosis patient is prescribed nebulised polymyxin in combination with piperacillin prescribed intravenously? What possible explanation may there be for this course of action?

Answer 38

Q1. Why has triclosan been banned in some countries? Triclosan has been banned in some countries primarily due to concerns over its contribution to antibiotic resistance and its potential harmful effects on health and the environment. Triclosan is an antimicrobial agent widely used in soaps, toothpaste, and other consumer products. Overuse of triclosan may promote the development of resistant bacteria, and there are also concerns that it could disrupt hormone function in humans and accumulate in the environment, negatively impacting aquatic life. Q2. How do bacteriostatic antibiotics treat infection, given that they do not kill bacterial cells? Bacteriostatic antibiotics work by inhibiting the growth and reproduction of bacteria, rather than directly killing them. This gives the immune system time to mount a response and eliminate the infection. By preventing bacteria from multiplying, bacteriostatic drugs help control the infection while the body’s natural defenses clear the pathogens. Q3. What does “serendipitous discovery” mean? Serendipitous discovery refers to the unexpected or accidental finding of something valuable or useful while searching for something else. In the context of antibiotics, many important drugs, such as penicillin, were discovered by chance rather than through targeted research. Q4. Why are there so many antibiotics that act on the cell wall, and so few that act on nucleic acids? The bacterial cell wall is an excellent target for antibiotics because it is unique to bacteria and not found in human cells, minimizing damage to host tissues. Drugs targeting cell wall synthesis can inhibit bacterial growth without affecting human cells. On the other hand, nucleic acid synthesis pathways are more similar between bacteria and human cells, making it difficult to design antibiotics that specifically target bacterial enzymes without harming host cells. Q5. How can infection be managed by addressing stages 1 and 2 of the infection process? Infection can be managed by: Preventing colonization (Stage 1): Using strategies like vaccination, hand hygiene, and barrier methods to stop pathogens from attaching to host cells. Inhibiting invasion (Stage 2): Employing antimicrobial agents and immune-enhancing therapies to prevent pathogens from penetrating tissues and spreading within the body. Addressing these stages reduces the likelihood of the infection becoming established and spreading. Q6. Which antibiotic class corresponds to the following target sites? Topoisomerase: Fluoroquinolones (e.g., ciprofloxacin) Peptide bridge: Glycopeptides (e.g., vancomycin) Translocation: Macrolides (e.g., erythromycin) Transpeptidation: Beta-lactams (e.g., penicillin) 60S ribosome subunit: There are no antibiotics that specifically target the 60S ribosomal subunit because it is part of the eukaryotic ribosome, not the bacterial ribosome. Folic acid synthesis enzymes: Sulfonamides and trimethoprim Q7. What does antibiotic resistance actually mean? Antibiotic resistance refers to the ability of bacteria to survive and multiply despite the presence of antibiotics that are meant to inhibit their growth or kill them. It means that infections caused by these resistant bacteria become much harder to treat and may require alternative medications or higher doses of antibiotics. Q8. Identify an infectious disease where resistance has risen disproportionately in recent years. Neisseria gonorrhoeae (the bacterium responsible for gonorrhea) has seen a disproportionate rise in resistance in recent years. This organism has developed resistance to nearly all antibiotics traditionally used to treat it, including penicillin, tetracycline, and fluoroquinolones, and more recently, third-generation cephalosporins, which were considered the last effective treatment options. Q9. Follow-up question: there was a controversial omission on this list that has now been included – can you guess what it is? The controversial omission that has now been included on the list of priority pathogens is Mycobacterium tuberculosis. Initially, TB was not included in the general list of antibiotic-resistant bacteria because of its unique treatment protocols, but its inclusion became necessary due to the rise of multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB). Q10. The newest drug, bedaquiline, is used for which microbes/disease? Bedaquiline is used to treat multidrug-resistant tuberculosis (MDR-TB). It specifically targets Mycobacterium tuberculosis by inhibiting the ATP synthase enzyme, which is essential for the bacteria’s energy production. Q11. What would you hypothesize are the function(s) of side chain variations in antibiotics? The side chain variations in antibiotics can: Alter spectrum of activity: Allow the antibiotic to be effective against different strains or types of bacteria. Enhance stability: Improve the drug’s resistance to bacterial enzymes that break down antibiotics. Increase potency: Improve the antibiotic's ability to bind to its target. Reduce side effects: Minimize toxic effects on human cells. Q12. Why does the clavulanic acid component of co-amoxiclav have to have the described properties? Clavulanic acid acts as a beta-lactamase inhibitor. Its properties allow it to bind to the beta-lactamase enzymes produced by bacteria, preventing these enzymes from breaking down the antibiotic (amoxicillin). This helps the antibiotic remain effective against bacteria that would otherwise be resistant. Q13. What bacterial genus is most commonly associated with endocarditis? The bacterial genus most commonly associated with endocarditis is Streptococcus, specifically Streptococcus viridans group and Staphylococcus, particularly Staphylococcus aureus. Q14. Why are there fewer antibiotics available for obligately parasitic bacteria? Obligately parasitic bacteria have a close dependency on the host's cellular machinery for survival and reproduction. Since these bacteria share many metabolic pathways with their host cells, it is more challenging to develop antibiotics that specifically target them without harming the host. Q15. Antibiotic resistance is driven by selective pressure – if patients were not being prescribed the drug, where was all the resistance coming from? Resistance can arise from: Agricultural use of antibiotics: Antibiotics used in livestock can promote resistance, which can transfer to human pathogens. Environmental contamination: Antibiotics released into the environment can select for resistant bacteria in soil and water. Horizontal gene transfer: Bacteria can acquire resistance genes from other bacteria through mechanisms like plasmids, even without direct exposure to antibiotics. Q16. A cystic fibrosis patient is prescribed nebulized polymyxin in combination with piperacillin prescribed intravenously. What possible explanation may there be for this course of action? This combination is likely prescribed to treat a Pseudomonas aeruginosa infection, common in cystic fibrosis patients. The nebulized polymyxin targets the lungs directly, achieving high local concentrations against the bacteria in the airways, while intravenous piperacillin ensures systemic coverage to treat any spread of infection. This approach also reduces the likelihood of resistance development by using two antibiotics with different mechanisms of action.