12 Microbiology Antimicrobial Chemotherapy

Tetracyclines

Its activity (how it kills or slows down microbes): block protein synthesis by binding to the 30S ribosomal subunit. Its spectrum: are very broad spectrum antibiotics, and therefore produce significant gastrointestinal side effects by altering the normal gut flora. Examples: It is the 4 ring structure!

Vancomycin

Its activity (how it kills or slows down microbes: targets the cell wall by inhibiting an enzyme necessary for cell wall synthesis. its spectrum (the range of microbes it affects): a narrow spectrum glycopeptide antibiotic Examples: is very important to the treatment of methicillin-resistant gram positive bacteria like Staphylococcus aureus. ( do not have to know this structure)

Gerhard Domagk

developed sulfa drugs, which block bacterial folic acid synthesis, and therefore kills them. - sulfa drugs were very important, but were soon over taken by another antibiotic.

Paul Ehrlich's Lab

developed the first effective treatment of syphilis called SALVARSAN, and because they were using chemicals to treat patients, he called this treatment CHEMOTHERAPY.

Synthetic drugs

drugs produced entirely by chemical reactions.

Semi-synthetic Drugs

drugs that are chemically modified in the laboratory after being isolated from natural sources.

Normal microbiota

so we normally carry around a bunch of harmless (and sometimes beneficial) microorganisms that we refer to as... - however we can sometimes pick up bad bacteria. Our _____ _______ will help to control the growth of those organisms, but when we take antimicrobial drugs, these drugs are generally not selective and can kill off our ________ _______. - to make it worse, the bad microbes may be resistant to the drug, so remain in the absence of competition... when they grow they can form a SUPERINFECTION.

Antibiotics

substances produced by the natural metabolic processes of some microorganisms that can inhibit or destroy other microorganisms.

Translation

the process of making new proteins and it happens at the ribosomes.

Antimicrobial Chemotherapy

the use of chemotherapeutic drugs to control infection.

Protease inhibitors

these inhibit HIV protease, which is necessary for the proper assembly of mature HIV particles. The problem with treating HIV with drugs is that the virus mutates so rapidly, new resistant strains appear extremely quick.

Selectively toxic

(the goal of any good antimicrobial), disrupts microbial metabolism or structures, leading to the death of the target microorganisms, without harming the patient. - The best targets for antimicrobial therapy are therefore those found only in microorganisms. - The closer the target resembles one of our own processes or structures, the greater the chance the drug has side effects.

Characteristics of the Ideal Antimicrobial Drug

1) Selectively toxic to the microbe but not to the host cells. 2) Microbicidal rather tan microbistatic 3) Relatively soluble; functions even when highly diluted in body fluids. 4) Remains potent long enough to act and is not broken down or excreted prematurely. 5) Does not lead to the development of antimicrobial resistance. 6)Complements or assists the activities of the host's defenses. 7) Remains active in tissues and body fluids. 8) Readily delivered to the site of infection. 9) Reasonably priced 10) Does not disrupt the host's health by causing allergies or predisposing the host to other infections.

More random facts!

But there are other protozoa that can cause infections, so we have other antiprotozoal drugs like metronizdaole.

Viruses can also disrupt nucleic acid synthesis...

Acyclovir can inhibit DNA synthesis in herpes viruses...and you probably have heard of AZT, which inhibits reverse transcriptase and therefore stops HIV and some hemorrhagic fevers from making DNA. - and in addition to fuzeon and AZT, people with HIV are treated with protease inhibitors.

A bunch of different types of Drugs that disrupt fungal membranes...

Azoles, like fluconazole, and econazole, are broad spectrum antibiotics that target the biosynthetic pathway that leads to ergosterol synthesis, and that disrupts the cell membrane (don't need to know structure).

Important information!

Because there is so much competition between microorganisms, most of our efforts are focused on isolating microbes with antibiotic activity, then isolating chemicals produced by these organisms. - we have a created alliances with a few really good microbial friends that have helped considerably in our war against infection... - Bacteria in the genus STREPTOMYCES are particularly good at producing antibiotics, but BACILLUS is also useful. - and of course many fungi are also on our side, PENICILLIUM and CEPHALOSPORIUM (now known as Acremonium).

There are several pathways though which bacteria can become antibiotic resistant:

Enzymes can chew them up before they do harm...receptors responsible for drug transport can be altered...and pumps can pump antibiotics out of cell before they do harm... - Microbes can decrease the binding sites for drugs by actively lowering the number of these sites (short term, non-genetic adaptation), or by altering the affinity of those sites for the drug (via gene mutation or acquisition of new genes). - in some cases the target metabolic pathway can simply be shut down, or an alternative pathway used until the drug goes away. So bacteria can lie in wait.

Penicillin

Its Activity (how it kills or slows down microbes): attack the cell wall. Its spectrum (the range of microbes it can affects): usually more effective against gram positive bacteria. Examples: Are also called beta-lactam antibiotics (because they all have a beta-lactam ring) but also have a thiazolidine ring. - A variable "R Group" is attached to the beta lactam group, and this "R" group confers specific activity to different penicillins.

Cephalosporins

Its activity (how it kills or slows down microbes): act by inhibiting bacterial cell wall synthesis. Its spectrum ( the range of microbes it affects): are relatively broad spectrum (resistant to most penicillinases and cause fewer allergic reactions) Examples: also have a beta-lactam structure..but have a different ring structure attached and have two "R" groups instead of just one. The generic names of these antibiotics often start with CEF-, CEPH-, or KEF- - some can be given orally, most are poorly absorbed from the intestine and therefore must be given PARENTERALLY, by injection into a vein or muscle. - it has been easier to develop new generations of cephalosporins because of the presence of two R-groups.

Bacillus Polymyxa

Its activity: Its fatty acids allow polymyxins to act as detergents and disrupt cell membranes. Its spectrum: polymyxins are narrow spectrum antibiotics limited by their toxicity to our kidneys. Examples: produces a chemical we called polymyxin, which peptides with special fatty acids attached to them. - polymyxin B and E are usually reserved for treating resistant PSEUDOMONAS AERGUINOSA infections or severe urinary tract infections.

Folic Acid

Its activity: SULFONAMIDES are synthetic antimicrobials which block bacterial folic acid synthesis and therefore bacteria cannot make DNA. Its spectrum: ? Examples: is necessary for the production of thymidine, which in turn is used to make DNA. - we get our folic acid from out diets, therefore these drugs don't stop us from making DNA.

Macrolide

Its activity: They bind to the 50S ribosomal subunit to block protein synthesis. Its spectrum: include erythromycin and clindamycin are broad spectrum and fairly low toxicity. Examples: antibiotics are named after their structure: a large lactone ring with sugars attached (That you should be able to recognize).

Quinolones

Its activity: these completely synthetic drugs block DNA replication Its spectrum: broad spectrum antimicrobials. Even at low doses these drugs inhibit most gram positive and gram negative bacteria, and are easily absorbed from the intestine, so they can be given orally. Examples: are chemically related to the antimalarial drug QUININE

Random fact!

Less than 100 years ago, one of every three children would die of infectious disease. 1 OF 3....=

Now fungi!

Remember we said ______ make ergosterol to put in their membranes, and this helps maintain membrane function? And remember WE make cholesterol, a similar molecule, but made by different enzymes in our cells. So if we could target the enzymes that make ergosterol, but one the ones that make cholesterol, we are in business! We can attack fungal membrane while leaving our own alone...And this is exactly what we do!

Random facts!

Remember when we were first talking about eukaryotic cell walls? many fungal cell walls are made of chitin, a tough covering of polymerized glucose. - well there are drugs (like ECHINOCANDINS), that disrupt the fungal cell wall and kill the fungus. - Echinocandins are used primarily against Candida and Aspergillus.

Remember pili?

We humans play a major role in the development of antibiotic resistant microbes...We used to liberally dispense antibiotics such as penicillin, even to patients that had viral infections...and we as patients tend to stop taking antibiotics before the complete course of antibiotics is done. - When we do that, we sometimes kill off the weak, susceptible microbes.

What do antimicrobials attack?

Well, because WE don't make cell walls, cell walls are great targets, and disruption usually lead to cell lysis...and if we poke holes in the cell membrane, microbes will have a hard time maintaining homeostasis or might also lyse... - in order to maintain homeostasis and reproduce, microbes must make new DNA and transcribe it into RNA, so those are great target processes...as is protein synthesis; no proteins no life! And because most microbes must make folic acid (we get ours from our diet), we can target that process too!

How do we solve the penicillin resistance problem?

Well, we can continue to develop new members of the family by changing the R- Group...and we can also add other chemicals to block the actions of beta-lactamases, such as clavulanic acid which is a beta-lactamase inhibitor that is mixed with amoxicillin and sold as Augmentin.

Microbes have been developing resistance as long as we have...

been developing antimicrobials. Bacterial strains resistant to penicillin were recognized in the 1940's. Bacteria can acquire resistance through spontaneous changes in their chromosomal genes, or by acquisition of entirely new genes ( called RESISTANCE FACTORS) through horizontal gene transfer...

So we have to consider the effects of...

a drug on the host, as well as the other members of the microbiota when treating our patients. In order to effectively treat infections, we should also break out the 5 I's and try to identify the microorganism causing the infection. If we can't do that ,we mostly rely on statistics. - for example if a child has meningitis, the majority of these cases are caused by STREPTOCOCCUS PNEUMONIA. So we start using the drugs that are effective against S. Pneumonia.

The Tube Dilution Test

a more sensitive test where microbes are grown in different concentrations of a drug...then examining the amount of growth at each concentration we can determine the MINIMAL INHIBITORY CONCENTRATION (MIC). - this information is important to determining the therapeutic index (TI) which is the ratio of the dose that is toxic to humans to the the MIC: TI= toxic dose/ MIC - when considering a bunch of different drugs for the treatment of a patient, the drug with the highest TI usually has the widest margin of safety.

Of course at some point we need to determine what drugs are effective...

against which microbes, and this turns out to be pretty simple. As long as the microbe grows on agar that is. We can take a pure culture of bacteria and spread it evenly over the surface of an agar plate. We can then drop the little disks that contain a known quality of an antimicrobial onto the bacteria on the agar plate. Overtime the antimicrobial diffuses into the medium, and if it is effective against the bacteria we have spread on the plate, the bacteria will not grow near the disk, where the highest concentration of the antimicrobial is. - this is called the Kirby Bauer disc diffusion test - by measuring the zone of inhibition ZOI, we can determine the relative effectiveness of antimicrobials against microbes. - once we have determined the ZOI, we can then refer to charts that let us know whether the bacteria is susceptible or resistant to the drug tested.

Antimicrobials

all-inclusive term for any antimicrobial drug, regardless of its origin.

Streptomyces

also produce another class of antibiotics, named for their 4 ring structures (that you should be able to recognize!)

The results of sensitivity testing can have important bearings on...

antimicrobial therapy. Once therapy has begun, it is imperative to monitor the patient's response, not only to identify deleterious side effects or allergic reactions, but also to observe the efficacy of the drug administered.

Narrow Spectrum (Limited Spectrum)

antimicrobials effective against a limited array of microbial types-for example, a drug effective mainly on gram-positive bacteria.

Broad spectrum (extended spectrum)

antimicrobials effective against a wide variety of microbial types.

Chemotherapeutic Drug

any chemical used in the treatment, relief or prophylaxis of a disease.

Sulfonamides

are good for treating shigellosis, acute urinary tract infections and some protozoan infections, and is very important in the treatment of pneumocystis pneumonia in AIDS patients.

Penicillin G and V

are the most important natural forms, but are narrow spectrum drugs that are more effective against gram positive bacteria than gram negative bacteria. - so semisynthetic, broad spectrum penicillins, like ampicillin and carbenicillin have been developed. - however, the microbes are rapidly evolving countermeasures to penicillins, and over 500 different enzymes that chew up penicillins have been identified from bacteria. - so we develop new penicillins that are resistant to these enzymes, such as methicillin or cloxacillin, but of course bacteria are developing resistance to these too.

When we have tested the patient's infection and antimicrobial therapy and still...

fails, it is usually because: 1) The drug cannot diffuse into the infected body compartment. 2) The presence of resistant bacteria not previously discovered in the patient's sample. 3) An infection caused by more than one pathogen, some of which are resistant to the drug.

Superinfection

for example, cephalosporin given to treat a urinary tract infection will kill the E. COLI that is the cause of the infection, but also the lactobacilli which helps create a protective acidic environment. - Cephalosporin has no effect on CANDIDA which will then thrive in the now nonacidic urinary tract.

Ok the Cell Wall is a...

good target, but so is protein synthesis. If a microbe cannot make proteins, it cannot maintain itself or reproduce, and will eventually die.

Paul Ehrlich

in the late 1800's, the German physician and scientist developed a number of dyes to stain cells... and noticed that some stuck to bacteria but not to eukaryotic cells. - He therefore thought, given the dye's specificity, that some could be used as "magic bullets" to specifically kill microbes and not harm the host.

The Microbial World...

is a bacteria-eat-fungi place, there is a constant struggle between microorganisms for resources and space; so every cell is looking for an edge. - Microbiologists started noticing that some microorganisms were able to inhibit the growth of other microorganisms when in close contact in culture.

The E Test

is a similar test that uses a strip containing the antibiotic, and eliminates the need to measure the ZOI.

Ciprofloxacin "Cipro"

is called a fluoroquinolone because its structure includes a fluorine atom. It was the drug of choice for treating anthrax, but the CDC now recommends doxycycline, which is as effective as cipro in treating anthrax, to delay the development of cipro-resistant bacteria.

The most common side effect of antimicrobials...

is diarrhea, usually through disruption of the normal gut flora. Most of our outer surfaces, including those of the large intestine, provide really inviting homes for microbes.

Metronizdazole

is used to treat mild to severe intestinal infections and hepatic disease caused by ENTAMOEBA HISTOLYTICA. It is also effective against GIARDIA and TRICHOMONAS, and even works well against some anaerobic bacteria!

Aminoglycosides

its activity (how it kills or slows down microbes): Is not well understood, but it is thought that they interfere with the ability of ribosomes to check their work, leading to errors in protein sequence and premature termination. its spectrum (the range of microbes it affects): relatively broad spectrum because they inhibit protein synthesis, but are particularly useful against aerobic, gram positive bacteria. Examples: are antibiotics composed of one or more amino sugars and a 6-carbon aminocyclitol ring (and you don't have to know this structure). These antibiotics are produced by STREPTOMYCES and MICROMONOSPORA. - word of warning...many aminoglycosides end with -mycin, but other drugs do as well so this is not a good way of remembering drug categories. - Streptomycin is the oldest member of this group and is being replaced by newer generations with less human toxicity. It is still however, the drug of choice to treat bubonic plague and tularemia, and also is pretty effective against tuberculosis.

Bacitracin

its activity (how it kills or slows down microbes): inhibits cell wall synthesis by blocking the addition of new cell wall subunits (don't need to know this structure) its spectrum (the range of microbes it affects): Narrow spectrum drug Examples: Is very toxic to us, so not used orally much but is found in a lot of topical creams like neosporin combined with other antimicrobials.

Rifamycin

its activity: inhibits RNA synthesis by blocking RNA polymerase. its spectrum: does not readily cross the cell envelope of gram negative cells and therefore is used primarily against gram positive bacteria. examples: is converted into rifampin. - it is also effective against mycobacteria including tuberculosis, and leprosy, usually given with other antimicrobials to delay the development of resistance.

Tapeworms

they are way more difficult, as they are much large and are animals (and therefore even more like us). To treat some of these guys we use mebendazole and albendazole. These are broad spectrum antihelminthic drugs that block microtubule function, which restricts the ability of the worms intestinal tract to take in nutrients, thereby starving them to death.

Viruses also pose special problems...

they rely on our cells for almost everything, so by trying to inhibit them, we can sometimes inhibit ourselves...so successful antiviral drugs target specific phases that will not interfere with our own cells function. Some drugs block adsorption and penetration of viruses to their host. - for example, fuzeon blocks the binding of HIV to its receptors on human cells, and tamiflu blocks the fusion of the influenza with human cell membranes.

Because so many microbes are becoming resistant...

to even out newest drugs, we are looking for novel ways to control infections. We are targeting the iron-scavenging abilities of some bacteria...using new molecular techniques to specifically block translation of messenger RNA molecules...and examining novel compounds such as defense peptides produced by other organisms. - we are also exploring how to disrupt how bacteria talk to one another, a process called QUORUM SENSING.

We have also been using antibiotics to treat our livestock prophylactically...

to keep them healthy...until we kill them. The problem is that a lot of those antibiotics end up in the environment at very dilute concentrations...so we end up exposing lots of microbes to nonlethal doses of these drugs, allowing them to develop resistance.

Prophylaxis

use of a drug to prevent imminent infection of a person at risk.

Sir Alexander Fleming

was looking at some of his culture plates contaminated with fungi and noticed that the fungal cells inhibited the growth of Staphylococcus. - he was able to isolate a compound from the fungus, PENICILLIUM. That compound was of course the wonder drug penicillin, which was more effective and caused fewer side effects than sulfa drugs.

Quinine

was the first successful treatment of malaria, a product that was extracted from the Cinchona tree. It has been used for decades against plasmodium. But it tastes horrible, it is somewhat toxic to us, and many species of plasmodium have become resistant to it. - second generation _____ are less toxic, but target different life stages of the plasmodium. For example, chloroquine targets the erythrocytic stage while primaquine targets the liver stage. - so no single drug is effective against every species or against every life stage.

When we develop new antimicrobials...

we have to worry about the toxicity to humans. As we have indicated, many of the current antimicrobials have side effects, ranging from merely cosmetic (like the staining of teeth by tetracycline)...to kidney and liver damage...to seizures and death! Frequently, a patient may be ALLERGIC to a drug, which occurs when the drug acts as an ANTIGEN which our immune system recognizes and develops a reaction to. - the first exposure to the drug might be without complications, but once sensitized, further exposure can lead to skin rashes, respiratory problems, and (rarely) anaphylaxis. Check out table 10.10 on page 281