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number 33

Done by Rawan Alkhabaz & Saja Alhijja

Corrected by

Doctor مالك الزحلف

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In the previous lecture, we’ve talked about second generation quinolone

(ciprofloxacin) which is the drug of choice for UTI and GI infection but it not work

on staph pneumoniae, then we mentioned respiratory quinolones (levofloxacin

and Gemifloxacin) that are used in case of community-acquired pneumonia

when hospitalization is needed, in addition to that, (sulfamethoxazole +

trimethoprim = cotrimoxazole) which serves as an alternative drug for

ciprofloxacin in UTI and GI infections, but we haven’t focused on it because of

its side effects.

But how do we deal with patients with G+ enterococci that developed resistance

to vancomycin?

- We use ceftaroline or the following two antibiotics

Linezolid

• it’s one of protein synthesis inhibitors that has special mechanism of action

somehow better than other protein synthesis inhibitors .(it shows a cidal

effect)

• Active against MRSA , VRE .

• Discovered before ceftaroline .

• its importance makes it a very expensive drug, 1500- 1200 JD.

• The Dr. said, there will come a time when this antibiotic use will

increase.why?

Imagine a patient with endocarditis, and has resistance to vancomycin or skin

infection from VRSA (more common in Yemen ). one of our choices is linezolid.

Linezolid can be taken IV or orally , on the other hand ceftalroline can only be

taken IV. its course is 14 days. it is oral and IV antibiotic, used for G+ resistant

strains.

in addition , it is bacteriostatic? but sometimes we don’t have another choice to

treat the patient in most cases.

Linezolid was approved to be used for vancomycin-resistant E.faecium

infections; nosocomial pneumonia; community-acquired pneumonia; and skin

infections, complicated or uncomplicated. It should be reserved for treatment

of infections caused by multidrug-resistant gram-positive bacteria.

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Daptomycin

• It is another drug that enters the cell wall and penetrates it .

• it’s bactericidal .

• it has main clinical limitation( explanation ): the surfactant fluid in respiratory

tract can deactivate it .

• Generally speaking, its uses are disassembled,specially, in respiratory tract

infection .

keep in your mind that this drug is not stable on surfactant in respiratory tract.

but we may use it in sepsis. According to dr malik, it is not clear where we can

put it as bactericidal.

However, Daptomycin is active against vancomycin-resistant strains of

enterococci and S aureus.

Note : go back to slides 113, 114,115,116 , read them by yourself because they

were not mentioned in the lecture and I’m not sure if they are included in the

exam.

Pregnancy is a critical period we can’t prescribe any antibiotic, we must ask

ourselves if that drug is safe for the pregnant lady or not ?

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This is an animal guideline, it depends on results of animal experiments and

some clinical trials.

Class A : it has been tested on pregnant ladies and has shown no adverse effects

on both fetus and pregnant women. (that is very rare).

Class B : it has been tested on animals and hasnot shown adverse activity

affecting the fetus or pregnant animal .

In addition , it has not caused congenital malformation of the fetus . (safe)

Class C : it was proved to be potentially harmless with no harmful effects, but

still there is a risk when it comes to its use. It has some indications,based on

animals tests, it might be harmful to the fetus or pregnant lady, though. this

harm is not very significant to prevent us from not prescribing the drug, and here

comes the idea of how benefits outweigh risks. in some cases, we should use

class C even if we know it would be a risk, especially ifour patient has a big issue

in a life-threatening situation, “quinolone causes arthropathy”

Class D: has shown teratogenic effects on fetuses of animals and humans. We

should never prescribe it during pregnancy except in special cases (relative

contraindications)

Class X : clear teratogen, either on animal or human fetus, for example :

Thalidomide was thought to be useful as anti-nausea drug in pregnant

women.it used to be prescribed during pregnancy before it was withdrawn

because of birth defects (such as short dolphin- like handsداء الفقمة) .

**Tetracycline should not be written at all because it has really harmful effect

(class d ).

** vitamin A is used for treatment of acnes , pregnancy should be avoided during

6 months after using it.

** safe antibiotic is group b

Note : don’t memorize the table.

This is the end of antibiotics wish u all the best .

Viruses

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Viruses are special microorganisams. They hijack the cell (يختطف الخلية), and force

it to produce its own proteins , nucleotides , envelope and budding out.The

infected cell becomes pathogenic in our bodies. you don’t usually find viruses

outside, but they are found inside the cell ; this is why it is difficult to give an

anti-viral drugs .

In the past,anti-viral drugs were given to kill the proliferating cells, those drugs

lack the selectivity; they kill both infected and non-infected proliferative cells

(hematomycin ,WBCs ,RBCs) which lead to bone marrow suppression .

Almost all cancer drugs cause bone marrow suppression(they target highly

proliferating cells)

Recently , Drugs have become more selective , We start this revolution in drugs

with one drug called “Acyclovir “.

Before you start treating viral infections, you must understand these points:

1- Viruses have different structures and components.

2- They produce different diseases.

Remember : viruses are either,

DNA viruses, such as: 1- Varicella-zoster virus (causes shingles). 2- Oral herpes (Herpes simplex 1 which causes herpes labialis) , genital herpes (herpes simplex 2 ) & herpes encephalitis. This virus is very common orally, and genitally in women. 3-Epstin Barr virus (linked to Burkitt lymphoma and nasopharyngeal carcinoma). 4-Cytomegalovirus causes viral Pneumonia which is lethal. It infects only immunocompromised patients (such as cancer patients). Or RNA viruses, such as: 1-HIV 2-Rhinovirus. 3-Hepatitis A+C. ( Hepatitis B is DNA virus.) 4-Influenza A+B+C.

3- Each virus has a specific drug , There is nothing called broad anti-viral

drug, it covers 2-3 viruses maximum .

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Except interferons (group of signaling proteins released by host cells in response

to pathogens) . We can synthesize it and give it to the patient as anti-viral that

covers most viruses , but they are very very bad drugs triggering immunity

response (inflammation). You don’t prescribe unless in some serious cases such

as Hepatitis C and cancer, benefits outweigh the risks

Revision of the common infection pathway of any virus (in most of

the cases)

1) Adsorption: the virus links to the receptor on the cell. 2) Penetration. 3) Uncoating. 4) Synthesis: in this step, the viruses use the cell machinery to produce new viruses (cell hijacking). Viral enzymes are used; such as DNA and RNA polymerases, reverse transcriptase, and RNA dependent DNA polymerase. RNA polymerase is used for the transcription of proteins. Some viruses integrate their genome into the cell DNA (using integrase), like HIV. After that, the genome is packed in the capsule. 5) Release.

- How do we treat simple viruses’ infections(Varicella-zoster ,

Cytomegalovirus , Herpes simplex)?

- By Anti-metabolites

Antimetabolites As we said , the idea of viral infection treatment was complex. And because the viruses are intracellular pathogens, we had to kill all dividing cells, infected or not, by antimetabolite drugs which are similar to chemotherapeutic drugs, with very bad side effects.To overcome the virus we have to fool it through “False” DNA building blocks or nucleosides. A nucleoside consists of a nucleobase and the sugar deoxyribose. In anti-metabolites, one of the components of nucleoside is defective. In the body, the abnormal nucleosides undergo bioactivation by attachment of three phosphate residues.

Acyclovir The idea of the drug is to select or find a way to select the infected cell.

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It is an antimetabolite antiviral, which means that it inhibits the synthesis of DNA. It resembles nucleosides structure; they look like Guaninebut slightly different. (notice the structure in the slides). The Antimetabolites (like Acyclovir), act as false nucleosides; when incorporated within the viral DNA, they block the continuation of replication, blocking transcription, so the virus cannot replicate anymore and this is called chain termination. What actually happens is that viral polymerase thinks that this is a true nucleoside; so it incorporates into the DNA and stops the transcription because it is not an actual nucleotide.

What is so special about acyclovir? Selevtivity. Before Acyclovir, we had a problem with specificity. The virus gets into the cell and hijacks its machinery, the only solution was to get rid of the virus by kill the cell, but because the drugs were not selective,non-infected replicating cells were affected, as well. Most of the antimetabolite drugs are nucleoside-like, to become nucleotide-like and interfere with the viral DNA, three phosphate groups have to be added to these structures by the enzyme kinase.

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Kinase Kinase Monophosphate Diphosphate Triphosphate nucleoside

To appreciate the importance of acyclovir, we are going to compare it with older antivirals.

Other antivirals : Idoxuridine , Trifluridine , Edoxudine , Vidarabine .

Acyclovir

Old generations depend on the cellular Thymidine kinase of the host; it will inhibit the viral DNA polymerase and the human DNA polymerase specially in replicating cells (such as bone marrow).

Acyclovir is only recognized by the viral Thymidine kinase; acyclovir is only activated (1st step of phosphorylation) in infected cells and does not affect the replication of normal cells. * Acyclovir is 30 folds more potent against viral enzymes than against host enzymes

Toxic to replicating cells of the host causing bone marrow suppression (very bad)

Not toxic , there is no bone marrow toxicity because200x affinity for viral thymidine kinase to activate drug.

No longer used Very commonly used

Note: the selectivity of kinase is only observed in the kinase that mediates the initial phosphorylation step which turns the X nucleoside into an X-monophosphate. The remaining two steps are mediated by cellular kinases in both acyclovir and the other groups of antivirals. Acyclovir is a pro-drugthat requires an activation.However, it is gonna be

activated only in the virus because the virus is inside the cell (Only cells with

virus kinase-activity can activate Acyclovir).

Acyclovir is active against: Herpes simplex and Varicella-zoster. It is rapidly broken down in cells. It is orally active and relatively non-toxic systemically. Itsspectrum is not wide, it works on DNA not RNA viruses.

To produce complete Acyclovir , it should be first converted it into AcycloGMP

by Thymidine kinase .

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Then AcycloGTP is eventuallyformed (complete Acyclovir with 3 phosphate groups). .

Acyclovir is used to treat:

1-Chickenpox:

Not common because of vaccination after one year of age.

ZoviraxisDOC to treat people above 45 , under one year and immuno-

compromised patients who haven’t been vaccinated.

2-Herpes simplex infections: (genital herpes, and herpes encephalitis).

Oral labials HSV1 : If you have herpes labialis infection then the doctor will ask you wether you wanna take acyclovir for (5-7) days or not to take it , because the usage of antiviral drugs does not really cure the infection, It just reduces the duration of the infection by 1-2 days and the recurrence of infection. Usually we treat labialis by giving Acyclovir (200 mg 5 times a day or 400mg 3 times a day) for seven days to reduce the duration by one day, in addition to the reduction of therecurrence . Therefore, treatment is not necessary unless the condition is severe.

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If the doctor gives a DNA synthesis inhibitor, the virus may have already been spread and the drug will not be active. To prescribe an active treatment against viral infections, you have to treat the patient from the beginning, beforethe virus spreads throughout the body (the spreading takes 36 hours after the manifestation of symptoms) In genital herpes cases HSV2 :(very common in the west) Oral acyclovir has multiple uses. In first episodes of genital herpes, oral acyclovir

shortens the duration of symptoms by approximately 2 days, the time to lesion

healing by 4 days, and the duration of viral shedding by 7 days. In recurrent

genital herpes, the time course is shortened by 1–2 days the one and half day is

critical because genital herpes is severe. You have to treat it:

1- To reduce symptoms by 2days (without treatment, it takes 7days)

2- Reduction of load.

3- To prevent reccurant.

Ladies suffer 30% more than men.

In the treatment of encephalitis Acyclovir is given.