Classification of antimicrobial agents:

بسم هللا الرمحن الرحمي Classification of antimicrobial agents: We can classify antimicrobial agents according to: 1. Mechanism of action 2. Chemical structure ( but it's very difficult, so it will follow mechanism of action: Antibiotics which act on cell well, and those which act on plasma membrane, DNA, RNA, interfering with a metabolic pathway and so on ) 3. Antimicrobial activity : with respect to the spectrum of activity they are classified into: - Narrow spectrum: cover a few number of microbes (bacteria), and certain antimicrobials are only effective in certain infections, the best example is "isoniazid" which is only effective in T.B (tuberculosis), why? Because they only act on Mycolic acids and Mycolic acids are only present in mycobacteria T.B. Aminoglycosides are bactericidal, widely used, considered as strong antibiotics, but why are they narrow spectrum? Because they are only effective in gram ve microorganisms and ineffective against gram +ve microorganisms. (narrow spectrum doesn t mean they are weak or less potent, the idea is that they cover a few number of microbes). - Broad spectrum: they cover more bacteria, and can even cover parasites. Whenever we say broad spectrum the antibiotic is strong theoretically speaking, stronger than a narrow spectrum antibiotic and so on. But this has nothing to do with whether the antibiotic is cidal or static. If you remember that the "mechanism of action" is likewise, it has nothing to do with whether the antimicrobial agent is acting on the cell wall or plasma membrane or whether it has a narrow spectrum or broad spectrum. (cover gram +ve & -ve cocci & bacilli) - Extended spectrum: When talking about Penicillins, we will find that antipseudomonal are listed under extended spectrum Penicillins, which cover this nasty organism (pseudomona) which is not that easy to kill or inhibit its growth. ( cover some microorganisms that are hard to eradicate) So we classified them into narrow spectrum, broad spectrum, extended spectrum according to the number of microbes they cover. General considerations: The first question that you have to put in your mind: whether or not the antibiotic is indicated. P a g e 1

Antibiotics are widely "abused", not in a sense that will lead to addiction (some think that abuse of antibiotics will lead to addictionthis is wrong) "abuse" could be applied to all drugs. Antibiotics particularly have been widely abused, the best example is the use of antibiotics in the management of viral infections. When a patient with common cold goes to a doctor he shouldn't give him an antibiotic. Even antibiotics are not indicated as effective agents in viral infections. A viral infection is a self-limiting disease, it passes by itself. When you have a common cold before taking any drugs you should consider taking a rest and within 2-3 days the viral infection usually suppress.. So the first rule is : is the antimicrobial agent indicated The second major, important point is to achieve a minimal inhibitory concentration MIC at site of action capable of inhibiting growth or killing microorganisms without affecting host cells. (this is a major principal applied to all diseases not only infections). Antimicrobials are harmful drugs. It is very easy to take them as candy (by children). New drugs are not necessarily better than old ones. Remember when we discussed the discovery of sulfonamides in 1936, and they were widely used, then resistance developed, and even with the invention of new more antibiotics that have better activity, better spectrum as compared to sulfa drugs, they ignored the sulfonamides(for 10 years) they stopped using them and they started using newer antibiotics because they have many advantages and less side effects etc. but later on they returned back to sulfa drugs and they found out that even sulfa drugs nowadays are better than certain antibiotics. And vice versa; Macrolides were slightly used in the past, but nowadays the most commonly used antibiotics are Macrolides, they are strong, they cover a wide range of microbes. So remember that antibiotics are harmful, and new drugs are not necessarily better than old ones, they have the concept of drug choice. The concept of drug choice is still applied even to certain drugs that were discovered long ago before 1950s. Another major consideration is to identify the microorganism, which allows us to select a better specific antibiotic that is going to be highly effective against it. Sometimes there is a need to combine more than one drug, we'll talk about combination when it is needed. Factors affecting the selection of an antibiotic: 1. Causative microorganism (susceptibility): The lack of susceptibility guarantees therapeutic failure, i.e if the microbe is not sensitive to a specific antibiotic there is no way it can treat this infection. (there is resistance) P a g e 2

Selecting a specific antibiotic (and by antibiotic I mean any chemotherapeutic agent) is based on: - Clinical picture, sometimes even without going through that. Especially in our country, through the clinical picture patients don t go to a physician but to a pharmacist. Some antibiotics are expensive, reaching 3 J.Ds a tablet, and you need a whole course to avoid the major problems that usually face people in the state, like bacterial resistance. - Bacteriology examination: identification of the bacterio organism and at the same time you do a susceptibility test. A six years old patient with Tonsillitis goes to the doctor with fever and pain in throat. The proper management (based on clinical picture) is to take a sample related to the site of infection, in tonsillitis you take a swab from the throat of the patient and you immediately start the patient on antibiotics applying the concept of drug choice I know what is best for tonsillitis so I start the patient with it. Meanwhile I ask the patient to come back in three days, and I send the swab for culture and sensitivity test. So after three days the patient comes back to the doctor, what concerns me is the health of the patient, if the patient improved on the antibiotic I placed him on then that's what I need, I even ignore the result of the lab(even if the lab result says that the bacteria is resistant to the antibiotic the patient is taking). But in most cases usually the clinical picture goes with the lab results. Now the problem is when I place the patient on an antibiotic but he is not improving, here I look at the lab result, I find that the bacteria is resistant to the antibiotic I placed the patient on so I change it, but with what? I choose one of the antibiotics that the lab result says the bacteria is sensitive to. - Serology: identification of specific antibodies against specific microbes. - PCR Polymerase Chain Reaction that could identify the DNA of the microbe. So nowadays we have advanced techniques by which we can identify microbes but they are a little expensive, but it is better to identify the microorganism and accordingly choose a specific antibiotic. 2. Pharmacokinetic factors: - Site of infection: if you have meningitis you need an antibiotic that can reach the central nervous system, likewise if you need it to reach the vitreous body of the eye, the prostate etc. - In the case of renal disease; if the patient has some renal dysfunction and the drug is excreted by the kidney you have to be careful, choose another antibiotic that is excreted by the liver for example, but if there is no way except prescribing that particular antibiotic at least you have to adjust the dose. There are certain antibiotics that are very toxic to the kidney when accumulated- like Aminoglycosides. P a g e 3

In the case of liver disease, likewise, if the drug is excreted/metabolized by the liver and the liver is lazy or has some dysfunction, be careful not to prescribe antibiotics that are excreted or metabolized by the liver or at least adjust the dose if they are highly indicated and there's no way for treatment except by giving that antibiotic, like: Erythromycin (one of the macrolide antibiotics),and tetracycline. One has to be careful with such drugs in patients with liver impairment. - Rout of administration: parenteral Vs oral The most convenient rout of administration to the patient is oral, and the parentral rout is not that convenient. But again if we have no choice we give parentral( IV for example) if we want the antibiotic to reach the blood or nerves etc. 3. Toxicity and side effects of antibiotics, a patient who is allergic to a certain antibiotic it's contraindicated to give it to him, except in certain situations. 4. Interactions with other drugs, a lot of antibiotics can be given in combination. One has to be careful about what sort of interactions can occur between these drugs, and hence adjust the dose, or giving such drugs at different times. 5. Cost 6. Host factors: - Age: newborns and old people( extremes of ages) have less kidney and liver function compared to adults (even though they are normal), and it is best to calculate the dose based upon the body weight as we mentioned in the introduction. - Allergic reaction to a given antimicrobial agent. Allergy is considered an absolute contraindication to all antibiotics, if the patient is allergic to a certain antibiotic absolute contraindication. So we ask the patient to carry a card and if she/he is allergic to that antibiotic we will know in order not to mistaken giving that drug to such individual. In cases of traveling we have faced a lot of death cases in response to antibiotic administration with respect to an allergic reaction reported in many patients, because the physician doesn t know, and for example if the patient is in coma and nobody from the family is with him, the doctor gives him this antibiotic and this will lead to severe anaphylactic shock and death. (before giving any patient benzylpenicillin we have to do an allergic test even if he swore that he took it before in his life) - Host defense mechanisms ( static Vs cidal) There are certain individuals whose immune system is compromised, like HIV patients, malnutrition, poor hygiene, advanced age, patients with neutropenia and anything that leads to suppression or decrease in the immune response of the patient, one has to be careful with them, this will affect the selection of antibiotics. Here we need to use cidal rather than static drugs. P a g e 4

7. Genetic factors: The best example is with those individuals who have what is known as G6PD (glucose 6 phosphate dehydrogenase) deficiency, if those individuals receive certain food( like (فول or more importantly certain drugs, there is a list of drugs that are contraindicated with them, if they are given to such individuals severe hemolysis occurs. This enzyme stabilizes the membrane of RBCs. This case is difficult, the doctor must be told that the patient has G6PD deficiency (its not like allergy) you can do some essay in measuring the enzyme for example, but this is not done. That s why a patient has to carry a card all the time, written on it the drugs he is allergic to, whether he has diabetes or HIV or hypertension etc. *note: diabetics may experience two types of coma: hypo (more dangerous) or hyper. Drugs that can lead to severe hemolysis if they are given to patients with this deficiency (G6PD deficiency): nitrofuratoin, chloramphenicol,sulfonamides. 8. In the case of pregnancy: Streptomycin, one of the aminoglycosides, if given to a pregnant lady it will cause deafness for the newborn. Drugs pass through the placenta through simple diffusion, so doctors should be careful with some antibiotics that may cross the placenta to the baby. This also applies to lactation, certain drugs are secreted to breast milk by passive diffusion, so newborns with G6PD deficiency develop severe hemolysis and death may occur. Some antibiotics are contraindicated during pregnancy such as sulfanomides, but there are other alternatives that can be given but we have to be aware of certain drugs that can lead to severe toxicity to the baby (or Lady). We have to consider the risk/benefit ratio, if we don t have other alternatives except streptomycin or aminoglycosides that should be given to a pregnant lady then we have to take the risk (because the incidence for congenital malformation is very low otherwise they wouldn t approve the drug) and monitor the baby (if we don t give the drug the mother would die as well as the baby) if any problem happens to the baby abortion is indicated. 9. In lactation if the drug is highly indicated then the solution is very easy we just ask the lady to stop breastfeeding the baby during the course of antibiotic. You can come up with solutions to these problems by yourself, you either change the antibiotic, or select a specific antibiotic, or if it is highly indicated you combine two drugs(synergism), decrease the doses etc. 10. Local factors at site of action, many things may lead to the abuse of antibiotic particularly abscesses which are treated only by excisions or incisions and drainage of the pus because the antibiotics do not reach the abscess (you open the abscess then drain the pus and then you can give antibiotics after that) but you can t treat abscesses by antibiotics. Abscesses are both external and internal (inside the body). P a g e 5

Bacterial resistance: We as humans have resistance for zenomycin, environmental toxins, drugs. So we have certain defense mechanisms in our body, the bacteria is likewise. Bacterial resistant occurs when: Clinical condition of host is impaired. Normal flora have been suppressed. Interrupted or inadequate treatment; the drug isn t given in proper doses or improper time. More frequently in certain types of bacteria; gram -ve bacteria possess an outer membrane and cytoplasmic membrane tough cell wall as compared to gram +ve, preventing passage of antibiotics through pores. Widespread use of broad spectrum antibiotics. In poor environmental setting of host: because these people don t take the antibiotic adequately, the same proper dose and the same duration. Mechanisms of bacterial resistance: 1. Natural resistance: if a drug works on the cell wall and there is no cell wall, or if a drug acts on protein synthesis and the bacteria has very rigid cell wall so the antibiotic can't enter the cell. - absence of specific metabolic pathway that is inhibited by an antibiotic or absence of a specific protein that is hit by a specific antibiotic. No presence of that enzyme or protein in the bacteria, penicillins bind to specific proteins on the bacteria called penicillin binding proteins, alterations on these binding proteins may lead to some sort of resistance - the need of the antimicrobial agent at site of infection in concentrations above the blood levels of that particular antibiotic is considered a mechanism of resistance. To overcome this type of resistance the drug has to be given in very large doses which leads to severe side effects 2. Acquired resistance(more common); microorganism is previously sensitive to the antibiotic but later on resistance becomes to that particular drug, this could occur as a result of - genetic change (mutations occur with time) so the genetic material is changed for one reason or another. - Adaptation. Production of certain enzymes that can break down the antimicrobial drug, for example: B-lactamases; which represent a problem with the use of B-lactame antibiotics. Infectious or multiple drug resistance through: Transduction: by bacteriophage which are viruses that transfer chromosomes or DNA that may result in resistance from one bacterium to another. P a g e 6

Transformation: transfer of DNA responsible for resistance from environment to bacteria, the bacteria releases that particular DNA and another bacterium will grab it and acquire resistance. Conjugation: Passage of resistant genes from cell to cell by direct contact. Most of resistance is acquired due to misuse or abuse of antibiotics e.g. improper dose. It is 100% proved that improper use of antibiotics could lead to more incidence of resistance by bacteria. Examples on mechanism of resistance: 1- Beta lactamases 2- Changing structure of target site, ex: Penicillin Binding Proteins 3- Preventing cellular accumulation of antibiotic by altering outer membrane proteins. The antibiotic enters the bacteria and there are transporter systems (called efflux pumps) in the bacteria that will lead to expel of the antibiotic to the outside. 4- Changing the metabolic pathway that is being blocked. 5- Overproduction of target enzymes: the enzyme was hit by the antibiotic but the bacteria can produce more of that enzyme leading to some sort of resistance. 6- Mycoplasma lacks a cell wall making it irresponsive to penicillin that acts on the cell wall. 7- Sulfadrugs (work on converting the para amino benzoic acid(paba) to folic acid) so the bacteria that obtains the acid from outside is resistant to such type of chemotherapeutic agents. Combined Therapy The best treatment is by giving one drug, but sometimes we need to combine drugs. Indications of combining antibiotics: - To obtain synergism or reduce the dose of a toxic drug. We have a toxic drug we have to reduce the dose, the reduction leads to reaching ineffective concentration more frequent and more incidence of resistance due to reducing the dose. You can combine 2 drugs, you reduce the dose of both of them so they synergize together in order to achieve good antimicrobial activity against the microorganism without affecting the incidence of resistance. - Treating mixed infection: You have 2 microorganisms with different sensitivities which is common for example 2 bacteria, the first one is sensitive to penicillin and the other one is resistant here you need to choose 2 different antibiotics. **even in mixed infections: 2 drugs are better than 3 or 4...etc - Treat infections at different anatomical sites: For example you may have tonsillitis and at the same time meningitis, if you can hit both with one drug, it is excellent. If you can t, you need to give more than one drug together. P a g e 7

- Treat infections of unknown etiology(cause): In some serious infections, we can t identify the microorganism We do all the tests (serology, culturing to make a sensitivity test for the specimen taken from the patient depending on the site of infection), and we don t know the organism the infection is of unknown etiology but we are sure a little bit that it is an infection so in this case sometimes one antibiotic is not that much of value, so we need to combine more than one drug together especially in patients with AIDS, agranulocytosis or neutropenia Outcome of combined chemotherapy: 1. Indifference: if you give 2 drugs that don t affect the kinetics of each other and this is what we want. 2. Antagonism: one drug could antagonize the other You have to be familiar with this, for example if you have a condition that requires combined therapy be careful not to combine 2 drugs that will antagonize the effects of each other. *it is said that cidal and static drugs shouldn t be given together, this is not the case always but sometimes it makes sense ** Static drugs will produce reversible inhibition of growth of microorganisms ** Cidal drugs will kill the microorganism, produce irreversible inhibition of growth. So if you give a cidal drug, it will kill the microorganism so the static drug will be ineffective, there is no need to give it(some sort of antagonism). 3. Synergism: penicillin and aminoglycosides Penicillin usually interfere with the function of the cell wall of the microorganism, it weakens the cell wall so the antibiotics which require to enter the cell will enter easily. Examples: Penicillin and aminoglycosides, Penicillin and tetracyclins which are protein synthesis inhibitors, there are many other examples. There are no contraindications of combining penicillin with aminoglycosides. Disadvantages of combined chemotherapy: Toxicity: although you are using lower doses but still the antibiotics are associated with many side effects that will be mentioned later. High costs. Prophylactic use of antibacterial agents: Prophylaxis: protecting healthy individuals or giving antibiotics to healthy individuals. It is common sense in certain highly contagious diseases, the best example is TB, TB is highly contagious disease, could be transmitted easily from one individual to another In this case certain agents that will protect healthy individuals against this nasty infection are necessary but not all people in AMMAN for example! Just to close contacts ( home, neighbors, hospital..) To prevent secondary infection in very ill patients. Very questionable and debatable issue, should we use antibiotics in individuals undergoing surgery for example? P a g e 8

They are indicated, we shouldn t! if infection occurs, we give the antibiotic but sometimes they are giving the antibiotic immediately after performing the surgery. It may make sense because our sterilizing techniques, (all over the world not just ours) no matter how much accurate and highly effective, can t totally prevent infection (infection is common for major surgeries). *Transplantation: Diabetes is treated 100% by pancreatic implantation, implanting a normal pancreas from a donor a dead person in a diabetic person. This is a major operation, rejection is common with transplantation of any organ. *skin transplantation: in cases of burns, taking a graft from a place to another from the same individual. Incidence of infection is high in these cases, so the doctor agrees that the patients should be given antibiotics. *delivery: the doctor disagrees with giving antibiotics in these cases but it is common now, here and outside after delivery, especially in nullipara or the first delivery for the lady. They do episiotomy: cut a little part of the vagina in order to expand earlier for easier delivery, this could be associated with high incidence of infection Sometimes the delivery could happen in homes or cars so the incidence of infection will be high, which leads to high incidence of mortality to both (the lady and the baby). *recurrent UTI: one of the nasty infections of the UTIs(urinary tract infections) especially in patients who are known as stone formers(they have stones in the kidney), those people have higher incidence of infection. In general, you take a urine sample, send it to the lab and do 3 tests: - Culture sensitivity - Serology - DNA Then you identify the microorganism, the sensitivity is accurate 100 %, you give the antibiotic no cure, change the antibiotic also no cure change it again no cure! (Recurrent UTI) UTI: common and not easy to treat, you will see these cases in the future. Prophylaxis is successful if: A single antibiotic is used, the best example is "isoniazid" in prophylacting patients with TB. Note: Isoniazid works on the cell wall Rifampicin works on the RNA polymerase and eventually in protein synthesis, also useful in TB. The dose required for prophylaxis is less than the therapeutic dose. The drug is needed or used for a brief period. If it is used for a long time, this could lead to many complications, it is not that much successful for a prophylactic agent to be used for a long period of time. Complications in antibiotic therapy: 1. Hypersensitivity: the major, common and most frequent side effect to antibiotics is hypersensitivity; it is not unique to penicillins only. P a g e 9

*Some people are allergic to aspirin (not an antibiotic) with sores all over the body not only rashes.(different types of allergy) Allergic reaction is a universal side effect to all drugs and specifically to antibiotics the most common. 2. Direct toxicity to certain organs 3. Super infection: due to the affection of the flora. Pseudomembranous colitis: unique side effect in the myocin, lincomyocin. Later on they called it antibiotic associated colitis: mainly due to suppression of the intestinal flora and over production of certain toxins, leading to severe colitis in the individual *a super infection is common. Good luck Done by: Lubna Hamdan, Maram Abu Halaweh, Sarah Qawasmeh. P a g e 11