num Doctor Done by Corrected by Maha AbuAjamieh Lara Abdallat Dr. Malik

Transcription

1 م num 26 Done by Maha AbuAjamieh Corrected by Lara Abdallat Doctor Dr. Malik

2 You should be familiar with the following points: (they were mentioned in the lecture) - Empirical Therapies : 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 Therapies: 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. - Bactericidal (kills bacteria) and Bacteriostatic(inhibits bacteria and prevents bacterial growth )agents - Bactericidal agents should be selected over bacteriostatic ones for treatment of critical conditions and infections (such as endocarditis, meningitis, septicemia, sepsis, bacteremia - don t memorize them-), where the bacteria can be found all over the body (systemically). In other words, in hospitals, we don t usually give statics, we usually use the cidals. - MIC (minimum inhibitory concentration) of a certain drug depends on the microorganism type, because each drug has an MIC that is different from a bacteria to another)for example we cant say that the MIC of penicillin is 5! Because we didn t determine on what kind of bacteria the MIC is 5, is it for staph?strep?, this is why when you read an antibiotic s leaflet, you will see that the drug is given at different doses, depending on the type of the infection/ bacteria. - Bacterial gyrases are like humans topoisomerases which help relieve (the tight twisting/ the strain/ supercoiling) which is formed during replication by breaking and rejoining DNA strands, polymerases catalyze the synthesis of DNA by adding nucleotides to the (preexisting) chain. - Knowing the antibiotics names is not enough, we should know their spectrum of activity what bacteria is the antibiotic effective against?- - One more added microorganism to spectrum increases the antibiotic s likelihood to be indicated (esp. for empirical treatment)

3 - The major problem threatening the continued use of antibiotics is the development of resistant bacteria. But that doesn t mean that all bacteria are resistant, sensitive bacteria are still present and can cause infection o (e.g: penicillin G is still the antibiotic of choice (empirically), for patients that are diagnosed with strep throat which is caused by Streptococcus, streptococcus has not even developed beta lactamase activity yet!) - This slide is our reference in this course, it is of great importance, we know that there are many antibiotics and many brands; but which one to choose? Answer: based on a series of rational steps,we took basic idea about this in the previous lectures, we choose antibiotics according to site of infection, source of infection and the narrowest possible spectrum (the narrowest is the best as the doctor says) This slide is giving details about the site of infection

4 do Main molecular targets for antibiacterial chemotherapy (antibiotics): - External Integrity of the bacterial Cell Wall (Cell wall synthesis), They are generally bactericidal. They are the oldest clinically used, All β-lactam compounds, so named because of their four-membered beta lactam ring: penicillin, cephalosporins, monobactams, carbapenems, vancomycin (and his brother teicoplanin) Note : vancomycin is not a beta lactam In this sheet we will have some details about penicillin G, Benzathine Penicillin, Penicillin V, Aminopenicillins and beta lactamase inhibitors. - Protein synthesis Such as tetracyclines, macrolides, chloramphenicol, clindamycin and aminoglycosides, they are all bacteriostatic except aminoglycosides, aminoglycosides are cidals. bacteriostatic agents put the bacterial cells in a static state (permanent growth arrest) without undergoing cell death, this happens to our cells, too(senescence) 1) Why Aminoglycosides are bactericidal? They have a dual activity/ multiple mechanisms of action (in addition to interfering with protein synthesis, they can also affect the integrity of bacteria and the fluidity of its membrane) But the precise mechanism for bactericidal activity is not known. This possible

5 duality or the multiple mechanisms of action, might be true since there is no real resistance against aminoglycosides, (about 97% of E.coli are still sensitive to gentamycin), aminoglycosides are still used (but not orally) - Perturbation of nucleic acid synthesis They are called antimetabolites, There are some bacteriostatic and some bactericidal antibiotics in this group, here are some mechanisms, 1) In bacteria, folic acid synthesis pathway is really important for synthesizing bacterial nucleic acids, we have two enzymes (a reductase and a synthase) in this pathway, their inhibition can lead to inhibiting the synthesis of pyrimidines and purines (building blocks of nucleic acid) by either Sulphonamides or Trimethoprim Note: the names of enzymes are not important. 2) Another mechanism to prevent the synthesis of nucleic acids is by giving analogues of pyrimidines and purines (molecules that resemble them), then the polymerase add them to the nucleic acid chain 3) Inhibitors of gyrases/ topoisomerase (such as quinolones, they are really clinically great, resistance to them is difficult) while DNA is being continuously synthesized, coiling/ strains occur, here comes the gyrase to break and rejoin to enable the polymerase to continue its job, what quinolones do? When Gyrases start working by cleaving the supercoiling, the antibiotics (quinolones) trap it,in the moment of cleaving the chain, in a complex, the chain remains cleaved, with no enzyme to rejoin it! This gyrase is essential for bacterial cell, quinolones don t actually inhibit the gyrase itself, but trap it, so in a way the gyrase is the one which caused the bacterial death-poisining- (quinolones are strong bactericidal) 4) inhibitors of RNA polymerases, in respiratory system, such as anti-tb rifampicin,

6 Rifampicin has a cidal activity, the strongest *inducer* of cytochrome p450.(it is a high yield question) Cell wall inhibitors - These agents interfere with synthesis of the bacterial cell wall (mammalians cells do not have it). generally speaking these inhibit transpeptidases (remember from microbiology: they are also known as, PBP -penicillin binding proteins), they work by preventing the linkages (cross-linking) in the cell wall of bacteria when they are multiplying and synthesizing their cell wall, which will lead to leakage of the bacterial contents, and disruption of the osmotic pressure difference, thus these cell wall inhibitors are -bactericidal antibacterial agents- ((Vancomycin has a different mechanism of action, go to microbiology lectures if you d like to remember, but generally It has a unique mode of action inhibiting the second stage of cell wall synthesis of susceptible bacteria..)) - To be maximally effective, cell wall inhibitors require actively proliferating (multiplying) bacteria. As previously mentioned, these antibiotics cannot target already-synthesized cell wall, but they target the bacteria when they are dividing, when their cell walls are being synthesized, it is when transpeptidases are working on the two bacteria s cell walls after division. - A general Rule: although the combination of bactericidal with bacteriostatic is a theory (which is found in almost every book), we don t usually use it practically because if the cell wall was linked, there would be no use of the bactericidal, because if you gave your patient a bacteriostatic drug followed by a bactericidal drug, the

7 antibiotics activity would decrease as a result of drug-drug interaction. Think about it! What is the use of stopping the replication (no mutliplying), and then giving a bactericidal drug, the cell wall is already synthesized(no use!) this rule is only theoretical BUT it can be used in some cases, for instance in peptic ulcer, we might use erythromycin (static) and amoxicillin (cidal), The main forms of Penicillins resistance Resistance to penicillins and other β-lactams is due to one of these general mechanisms: 1. β-lactamases (penicillinases) which hydrolyse the lactam ring. β-lactamase production is particularly important in staphylococci, but they are not produced by streptococci. (streptococcus is sensitive) At least 90% of staphylococcus species in the West now produce β -lactamases. To overcome the problem, β -lactamase antagonists such as clavulanic acid which is a suicide inhibitor of the enzyme, are used. 2. reduction in the permeability of the outer-membrane of Gramnegative bacteria (remember: this outer membrane is not present in gram- positive bacteria) 3. mutations to the penicillin-binding proteins (transpeptidases). - ExtraNote: referring to point 2, it is true that gram-negative resistance can develop due to the impermeable outer membrane of their cell, but in this sheet, we will see that Beta-lactam antibiotics can cross the outer membrane and enter gram-negative organisms, but how? via outer membrane protein channels called porins. Penicillins: 1) The Natural Penicillin (penicillin G/ benzylpenicillin) Naturally-occurring benzylpenicillin (penicillin G) is active against some organisms but their main drawbacks are o penicillin G is sensitive to acid hydrolysis in the stomach, which means it has to be administered by

8 injection, but not orally administered because it is unstable in the stomach. o Its susceptibility to β -lactamases. (penicillinasesensitivity) o Limited activity against gram negatives. These, and other, drawbacks gave inspiration to the development of the semi-synthetic agents designed to be : 1) b-lactamase resistant 2) broad spectrum 3) extended spectrum (extended to include pseudomonas) the following lecture The natural Benzylpenicillin (Penicillin G) is Given IM or IV. Active against (its spectrum): most gram-positive bacteria (mainly streptococcus) with the exception of penicillinase-producing Staphylococcus aureus ( but active on staphylococcus without this -ase activity, which is not present in life nowadays) limited activity on gram negative bacteria, it is only active on some gram-negative anaerobes and most Neisseria species (such as Neisseria gonorrhoeae and Neisseria meningitidis) not active against most gram-negativeaerobic organisms Realistically-speaking, it is active on Neisseria and Streptococci, it has no actual staph. activity, it is not our drug of choice in patients with staph infections (because sensitive Staph are no (اللي استحوا ماتوا longer existent clinical uses of penicillin G

9 - Empirical Treatment for beta hemolytic streptococcal pharyngitis (aka, Strep Throat). This Strep Throat (pharyngitis), is characterized by the presence of white spots on the surface of the throat, why we can empirically use penicillin g? Because Streptococcus is the only cause of this strep throat, and penicillin G is active against streptococci. - Refer to the important slide (page 2) and see how penicillin G cannot be used empirically for patients with upper respiratory tract, urinary tract and ALL the other infections, we conclude that this penicillin G can only be used empirically to treat people with strep throat. - Streptococcal infections that include pneumonia, otitis media, meningitis, and septic arthritis. Penicillin G is used only as definitive therapy. o When a patient is diagnosed with meningitis, we don t use penicillin G empirically because it is true that Neisseria meningititidis and Sterptococci can be possible causes, but there are many other possible bacteria can cause meningitis which cannot be targeted by penicillin G, such as E. coli (refer to the slide in the second page) penicillin G is then effective against Neisseria meningitis (definitive for N.meningitis), meaning that if you are sure that Neisseria meningitidis is the cause of meningitis, you are allowed to use penicillin G o Another example is pneumonia, it is known that Streptococcus pneumoniae is the most common cause of it, but we cannot use it empirically because there are many other bacteria can cause it too - Penicillin G can be active on single microorganisms such as Clostridium tetani, and Corynebacterium diphtheriae, Treponema pallidum (syphilis), and Listeria monocytogenes. (in systems, we will have more details)

10 A student s question Q: can we use penicillin in the previous cases empirically? A: each one of the previous cases (Diptheria, Tetanus, Syphillis..) is actually caused by one known microorganism, but anyway, they are used as 1 st line drugs. - The autoimmune Rheumatic fever follows streptococcal infections, (so it might be a complication of strep throat), if patients were diagnosed with streptococcal infections more than once (repeatedly infected), the patient s condition might worsen, what is the solution? It is to prevent streptococcal infection by giving the patients penicillin g prophylactically (prophylaxis: treatment given to prevent disease.) daily,by injecting it from the day of diagnosis, so if a 6-year-old child was diagnosed, he will be given prophylactic doses till 21, it is used as streptococcal prophylaxis and to prevent the recurrence of rheumatic fever. - But due to the difficulty of giving a patient an injection of penicillin G daily for this long time, we found benzathine penicillin so we would be able to give this patient an IM injection once a month instead, as if it makes a reservoir, which takes 2-3 weeks for a sustained release, as discussed more below. Clinically, penicillin g is usually used in prophylaxis (rarely in treatment) 2) Benzathine penicillin Benzathine penicillin for intramuscular injection (IM) yield low but prolonged drug levels (injected intramuscularly because it is formed by adding something to penicillin that makes it colloidal) 1) A single intramuscular injection of benzathine penicillin, 1.2 million units, is an effective treatment for β-hemolytic streptococcal pharyngitis (strep throat)

11 Also prophylactic, given intramuscularly once every 3 4 weeks, it prevents reinfection and recurrence of rheumatic fever. 2) Benzathine penicillin G, 2.4 million units intramuscularly once a week for 1 3 weeks, is effective in the treatment of syphilis (compliance) (DON T memorize the number of units, you should only notice that we doubled it in the case of syphilis, because each bacterium has their own MIC -minimum inhibitory concentration- which is different from other bacteria s MIC, even for the same antibiotic. Syphilis needs more to be killed. 3) The natural Penicillin (penicillin v/ phenoxymethylpenicillin) Empirical treatment for beta hemolytic streptococcal pharyngitis. (strep throat) It is more acid stable, it is orally active but is less potent than penicillin G, more convenient to use it for children with strep throat, because it can be taken orally, (instead of injections) Adults with strep throat/ rheumatic fever, can use it if penicillin G is not available, It has the same spectrum as penicillin G but it is more active on anaerobes, (Peptococcus, Peptostreptococcus, Actinomyces) refer to the slide to check the names of bacteria Penicillin V often employed in the treatment of oral infection, where it is effective against some anaerobic organism. Penicillin V is the most frequently prescribed antibiotic for oral infections worldwide (because of its narrow spectrum) but we love to be unique! : ) It is the first choice in the treatment of odontogenic infections. (1) post extraction infection, (2) pericoronitis and (3) salivary gland infection. Dentists use it. 4) B-lactamase-resistant Penicillins

12 These include Cloxacillin, Flucloxacilin, Oxacillin, methicillin. methicillin is not available any more because of its side effects and it was the one to blame for bacterial resistance (extra: methicillin causes interstitial nephritis) MRSA is very common. (MRSA = methicillin-resistant Staphylococcus aureus) Antibacterial spectrum is the same as for penicillin G, but less potent and does cover staph producing beta- lactamase. This group was synthesized because staphylococcus became resistant to tetracyclineswhich were great targets to many gram positive and gram negative bacteria. Their use is restricted to treatment of infections caused by penicillins-resistant bacteria. Nonetheless, Many Staphylococci are now resistant to them. They cover both Streptococcus and Staphylococcus, they are good drugs to be used emipirically to skin,(also definitively), Skin Infections -as the slide shows- are caused mainly by Streptococcus pyogens, Staphylococcus aureus and Staphylococcus epidermis Hence, we don t use penicillin v, because it has no activity on staph 5) broad Spectrum Penicillins Aminopenicillins 1. These include Ampicillin, which is fairly well absorbed orally (usually injections), Amoxicillin which is very well absorbed (usually orally), and is prodrug (a biologically inactive compound which can be metabolized in the body to produce a drug) to ampicillin. Their antibacterial spectrum is the same as for penicillin G plus some Gram-negative bacteria. (aminopenicillins are made by adding an amino group to the penicillin structure which makes it more soluble in waterand enhances its ability to penetrate the outer membrane of gram negatives by entering the porins) Ampicillin and amoxicillin are among the most useful antibiotics for treating children suffering from infections caused by sensitive gram-negative aerobic bacteria, enterococci,

13 β-lactamase-negative H.influenza Aminopenicillins (Amoxicillin and Ampicillin) were developed to increase activity against gram-negative aerobes Gram Positive Gram Negative Penicillin susceptible Staph aureus Proteus mirabilis Penicillin susceptible Streptococcus Salmonella Viridans Streptococci Some E.coli Entercoccus sp. B-Lactamase-negativeH. influenzae Listeria monocytogenes 6) B-Lactamase Inhibitor Combos (Unasyn, Augmentin, Timentin, Zosyn) Developed to gain or enhance activity against B-lactamase producing organisms (some better than others). Provides some or good activity against: Anaerobes Bacteroides sp. Gram- S.aureus positive MSSA Gram- Neisseria negative gonorrheae Moraxella catarrhalis Klebseilla sp. Proteus sp. H. influenzae E. coli These can target those bacteria with beta lactamase activity such as staph, H. influenza or even E.coli Augmentin = Clavulanic Acid (a beta-lactamase inhibitor) + Amoxicillin Augmentin is the drug of choice to all upper respiratory tract infections except strep throat. We should thank Dr. Malik, our books and whoever invented Google and Youtube, at the end of semester.