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Eugene Sanders
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1 number 25 Done by م ها أبو عجمي ة OsamsaAlZoubi Corrected by - Doctor Dr. Malik

Antibiotic Misuse There are many ways of antibiotics misuse: Taking antibiotics when they are not needed: Antibiotics are antibacterial agents, they should be generally used for bacterial infections

2 Antibiotic Misuse There are many ways of antibiotics misuse: Taking antibiotics when they are not needed: Antibiotics are antibacterial agents, they should be generally used for bacterial infections but many people misuse them for viral infections (most common) and other microorganisms infections! note that these results are reported by CDC for patients in the US, the results are disastrous, what about our country? the percentages are certainly higher since there is no actual control on antibiotics prescription! When antibiotics are needed, they might be taken incorrectly: some patients stop taking when they feel better - not finishing the full course that is prescribed by the doctor (this can increase the risk of superinfections, which are mentioned in the previous lecture)- Sharing or using someone else s medicine, and saving antibiotics for future illnesses, there is a misconception, some people think that they can use one antibiotic for all infections, but the truth is that the bacteria that cause infections in the areas bellow and above the diaphragm are totally different.

3 resistant bacteria are found in cows meat if they are given antibiotics unwisely not only for preventing infections but also to increase their growth rate and for other commercial purposes, this resistant bacteria can be transferred to us via the food chain. A Real Example on misuse: (all the following will come in more details in the following lectures, don t waste your time memorizing them) One example on misuse is : ciprofloxacin (a quinolone) is still prescribed for teeth infections (+toothache) but ironically, most mouth infections are as a result of gram positive bacteria, but this ciprofloxacin is actually more active on gram negative bacteria, but don t doctors read antibiotics leaflets?? Well, some leaflets are outdated, because if they were updated, the antibiotic s indication will decrease $$ Why is Antibiotic Misuse a Problem? (1) Antibiotics become less effective and may not work the next time you use them. (2) Improper use of antibiotics leads to more antibiotic resistant bacteria. (3) Antibiotic resistant bacteria can be spread throughout the community and from person to person (4) Causes Disturbances in the balance of the Normal Flora. (( Our great colleague Osama AlZoubi gave this example to clarify what is exactly happening, the normal flora of our Oropharyngeal area consists mainly of streptococcus (gram positive), H. influenza and some Neisseria (gram negative) and some Haemophilus (gram negative( if you are used to taking antibiotics, you are actually resulting in: 1- An imbalance between these microorganisms(normal Flora) 2- The repeated usage of these antibiotics is selecting for the resistance in some bacteria of this area by killing the sensitive ones.

4 One example on these resistant bacteria is the Streptococcus pneumoniae, if you got sick and this resistant bacterium left your oropharyngeal area and moved to your ear (because of the presence of an access to it through the Eustachian tube ), you would suffer from otitis media. Now, what gave the Streptococcus pneumoniae, the opportunity to replicate and colonize the Eustachian tube? The answer is, the presence of enough space and nutrients in the oropharyngeal area. What is the relationship between the antibiotic misuse, and giving space and nutrients for disease causing bacteria? We said that antibiotics cause imbalance between the Normal Flora, so Lets say Someone has misused a gram negative spectrum antibiotic (for example taking the antibiotic repeatedly and without medical prescription) such as Sebro Flucloxacillin, what will happen is the Gram negative bacteria such as Neisseria and Haemophilus will be killed, and that means giving space for the gram positive Streptococcus pneumoniae to replicate to dangerous amounts thus causing infection. Haemophilus Gram-Negative Neisseria Gram-Negative Streptococcus pneumoniae Gram-positive More Space and Nutrients

Now we have explained the first aspect of antibiotic misuse, the second aspect is as we mentioned above, The repeated usage of these antibiotics is selecting for the resistance in some bacteria of

5 Now we have explained the first aspect of antibiotic misuse, the second aspect is as we mentioned above, The repeated usage of these antibiotics is selecting for the resistance in some bacteria of this area by killing the sensitive ones, this is called the Selective Pressure. So as you can see in the illustration, the overtaking and misuse of antibiotics kills the sensitive bacteria and keeps the (Genetically mutated Resistant Bacteria ) alive, which multiplies and causes infections that are either untreatable, or they need a higher dose of antibiotics to kill them. So lets go back to our example, As a result of the misuse of antibiotics throughout history, we are increasing the dose of Augmentin (amoxicillin and clavulanate ) for children infected with Otitis Media, because the Streptococcus pneumoniae became resistant. So nowadays, instead of giving mg/kg/day dose of Augmentin, now we give mg/kg/day, and unfortunately some strains of Streptococcus pneumoniae have developed resistance mechanisms making them totally resistant to Augmentin. Check these articles, talking about the appearance of these dangerous resistant strains :

6 Remember that the child is not the only one who is in danger, he can pass those resistant bacteria along to the people around.. to the community! Don t use/ prescribe antibiotics unless you are facing bacterial infections, (bacterial infections are usually more severe, the patient becomes unable to move, suffers from severe pain especially in his joints, sleepiness and many other symptoms) Deep look to those who use antibiotics unnecessarily for viral infections : The results of a trial on patients with viral infection are shown above, the red continuous line represents patients using an antibiotic while the yellow dotted line represents those who took placebo capsules (sugar pills) for up to 10 days. The results indicate that healthy people will usually get better without antibiotic treatment. There is a myth which says that green sputum is associated with bacterial infection while yellow sputum is associated with viral infections, But this is not true, the colour of sputum cannot be used to differentiate between viral and bacterial infections and the colour of sputum should not be used to make a decision on whether to prescribe an antibiotic.

The common cold is usually caused by viral pathogens, symptoms include (cough, fever, sore throat and runny nose)symptoms may last up to 14 dayswith anaverage of 7days as shown above, and then the

7 The common cold is usually caused by viral pathogens, symptoms include (cough, fever, sore throat and runny nose)symptoms may last up to 14 dayswith anaverage of 7days as shown above, and then the common cold resolves without antibiotic treatment, so according to guidelines, wait two or three days until your body heal itself.. (the viral infection would stay 1 week with or without antibiotic) but you should take antibiotics for bacterial infections. Treatment with an antibiotic does not shorten the duration of illness, But the question is why do we feel better after taking the antibiotic?? It might be something psychological, something like the Placebo effect but with disastrous consequences (such as resistance) Most people, don t go to the doctor at their first day of infection but they go the second or the third day of infection, when the viruses flare up and the symptoms worsen, it is when most people start taking antibiotics, but

8 anyway -even if the patient is not using an antibiotic- the symptoms will spontaneously decrease after the second day of infection. As Shown Above Kinetics disturbance because of misuse MIC (minimum inhibitory concentration), the given antibiotic s concentration levels should be 4-6 times higher than the MIC. - If the patient was compliant, and he took the right doses, at the right time, (a steady state is reached because of compliance, by taking the successive doses of drug on time) - But what happens if our dear patient missed the dose or started to take the doses without consultation, or irregularly take them, the steady state would be disrupted as shown bellow. - The pink indicates subtherapeutic doses, ( which will lead to killing the good guys that protect us)

Therapies usually chemotherapies chemotherapy is a therapy that kills the target whether a microorganism as bactericidal antibiotics or human cells as anticancer drugs-, here are the therapies:

9 Therapies usually chemotherapies chemotherapy is a therapy that kills the target whether a microorganism as bactericidal antibiotics or human cells as anticancer drugs-, here are the therapies: Prophylaxis : Prevention, it is usually used for immunosuppressed people to protect them from infections such as diabetic old patients/ cancer patients who undergo chemotherapy, or those who are in direct contact with infected patients or in cases of pandemic diseases because if prophylactic doses are not given to them, infections might kill them. توق عيEmpirical Based on experience and, more specifically, therapy begun on the basis of a clinical educated guess in the absence of complete or perfect information. (it is given blindly/ no cultures are sent to lab) Definitive therapy The treatment plan for a disease that has been chosen as the best one for a patient based on tests made, in other words, you know exactly the cause of infection after getting results from the cultures you ve sent (or by sensitivity test) and then decide to choose the best antibiotic.

10 Post-treatment suppression therapy It is used after treatment to prevent recurrence of the infection, if you prescribed an antibiotic for 14 days, but after the 14 days, the infection came back, you should think of this type of therapy, (usually giving halfdose for a longer duration) Here are some examples on post-treatment suppression therapy, o ciprofloxacin, (a quinolone) is used for women with complicated, recurrent (4 times or more a year) urinary tract infections (UTIs) especially postpartum, we treat them with a dose 1000mg per day for 7 days, and after treatment they go on half-dose (500 mg per day) for 6 months Numbers are not for memorisation, only for clarification. NOTES about ciproloxacin: ciprofloxacin is contraindicated in children because of its side effects such as arthropathy UTIs are mainly caused by E. Coli and Staphylococcus saprophyticus o This therapy is also used for patients with 3-4 times a year recurrent ulceration in mouth, ( this ulceration is caused by a virus (Herpes simplex), so after treatment, an antiviral is given to patients as post-treatment suppression therapy) In the previous two cases, the problem is as a result of high load (the quantity of infective bacteria is high, it becomes dominant), there would be no balance (no competition on nutrients in the body), the infection proliferate because there is nothing to supress it.. - The spontaneous rate of mutation in bacteria is very low; about 1 in 10 million cells per division will be a mutant ( unlike us, bacteria have low rate), But if it was an induced mutation as a result of a certain stress such as antibiotics misuse, this would increase the rate. In addition to that, resistance genes from one mutant bacterium can move to others by plasmids - Upon treatment, no mutation occurs, because its formation takes time.

11 - clinical difficulties arise when the infecting bacteria are already drug resistant. What are the Bacterial resistance mechanisms? The four main mechanisms of resistance include: A) Production of an enzyme that inactivates the drug Penicillinases, Cephalosporinases, Carbapenemases, Extended-spectrum beta lactmases, there are about 300 types, the most important one is beta lactmase B) Mutations in the target macromolecule (Receptors) Mutation on binding sites, (MRSA) C) Induction of mechanisms to reduce accumulation of the drug Tetracyclines used to be active on gram positive and gram negative bacteria, but they are no longer used because of efflux pumps, to pump the antibiotics out (most bacteria are no longer sensitive to them, the only exception is mycoplasma because it has no cell wall, so there is no place for pumps expression) D) Multiple drug resistance involving multiple mechanisms of actions (mutations, enzymes and efflux pumps), so the microorganism is mutated with beta lactamases and efflux pump, there is no antibiotic active against it till now. examples: Multidrug acinetobacter, resistant E.coli, psuedomnas let s put all the mechainsms together: 1) Staphylococcus aureus became resistant to penicilllin by producing betalactamases, 2) we synthesised the beta-lactamase-resistant penicillins (oxacillin, flucloxacillin, cloxacillin, methicillin) 3) the bacteria responded to the synthesis of these beta-lactamase-resistant penicillins by mutating the binding sites (MRSA appeared and there were no drugs active on MRSA

12 4) we used vancomycin, but another another mutation occured (VRSA appeared), but the biggest problem is the Multiple-drug resistant bacteria (mutations, efflux, beta lactmase) Remember: MRSA- methicillin-resistant Staphulococcus aureus Best of Luck!

Burton's Microbiology for the Health Sciences. Chapter 9. Controlling Microbial Growth in Vivo Using Antimicrobial Agents

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