number 33 Done by Rawan Alkhabaz & Saja Alhijja Corrected by Doctor مالك الزحلف 1
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. 2
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 enterococci and S aureus. is active against vancomycin-resistant strains of 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? 3
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. (داء الفقمةhands because of birth defects (such as short dolphin- like **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 4
Viruses are special microorganisams. They hijack the cell الخلية),(يختطف 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. 5
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. 6
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,noninfected 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. 7
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. 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). Toxic to replicating cells of the host causing bone marrow suppression (very bad) No longer used Acyclovir 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 Not toxic, there is no bone marrow toxicity because200x affinity for viral thymidine kinase to activate drug. 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. 8
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 immunocompromised 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. 9
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. 10