Chapter 10 Antimicrobial Treatment

If the goal of chemotherapy is to disrupt the structure or function of an organism to the point where it can no longer survive, then the first step toward this goal is to?

Identify the structure and metabolic needs of a living cell

What is the Narrow Spectrum (Limited Spectrum)

Antimicrobials effective against a LIMITED ARRAY OF MICROBIAL TYPES

What is the Broad Spectrum (Extended Spectrum)

Antimicrobials effective against a WIDE VARIETY OF MICROBIAL TYPES

What is a chemotherapeutic drug?

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

What is Prophylaxis?

Use of a drug to prevent imminent infection of A PERSON AT RISK

Resistance occurring through horizontal transfer originates from plasmids called?

Resistance (R) Factors

Some infectious agents require ANTIMICROBIAL SENSITIVITY testing and some do not. Testing is essential in those groups of bacteria commonly showing resistance, such as?

Staphylococcus species (mrsa) Neisseria gonorrhoeae Streptococcus faecalis Aerobic, gram-negative intestinal bacilli

The greatest numbers of current antibiotics are derived from bacteria in the genera...?

Streptomyces and Bacillus and from molds in the genera Penicilium and Cephalosporium

What are Antibiotics?

Substances produced by the NATURAL METABOLIC PROCESSES OF SOME MICROORGANISMS that can inhibit or destroy other microorganisms

One of the most useful ways of categorizing antimicrobials, which you have already encountered in the previous section, is to designate them as either BROAD SPECTRUM or NARROW SPECTRUM. Broad spectrum drugs are effective against more than one group of bacteria, whereas narrow spectrum generally target....?

a specific group

The goal of antimicrobial drugs is either to?

disrupt the CELL PROCESSES OR STRUCTURES of bacteria, fungi, and protozoa OR to INHIBIT virus replication

Most of the drugs used in chemotherapy interfere with the function of?

enzymes required to synthesize macromolecules or they destroy structures already formed in the cell.

The ability to circumvent or inactivate antimicrobial drugs is due largely to the?

genetic versatility and adaptability of microbial populations.

Because the cells of fungi are eukaryotic, they present special problems in chemotherapy. For one, the great majority of chemotherapeutic drugs are designed to act on bacteria and are generally ineffective in combating fungal infections. For another, the similarities between fungal and human cells often means that drugs toxic to fungal cells are also capable of?

harming human tissues (see slide 39)

Above all, drugs should be SELECTIVELY TOXIC, which means they should?

kill or inhibit microbial cells without simultaneously damaging host tissues.

Chemotherapeutic agents are described with regard to their origin, range of effectiveness, and whether they are?

naturally produced or chemically synthesized

Additionally, microbes in biofilms often require different drugs than when they are?

not in biofilms

What are PREBIOTICS?

nutrients that ENCOURAGE THE GROWTH of beneficial microbes in the intestine

Examples of drugs with excellent selective toxicity are those that block the actions or synthesis of the CELL WALL in bacteria which is?

penicillins

What are PROBIOTICS?

preparations of live microorganisms that are fed to animals and human to IMPROVE INTESTINAL BIOTA **this can serve to replace microbes lost during antimicrobial therapy or simply to augment the biota that is already there. EX: yogurt

There may be a third mechanism of acquiring resistance to a drug, which is a phenotypic, not a genotypic adaptation. Recent studies suggest that bacteria can "go to sleep" when exposed to antibiotics, meaning they will slow or stop their metabolism so that they cannot be harmed by the antibiotic. They can then rev back up after the antibiotic concentration decreases. Sometimes these bacteria are called?

"persisters"

Antimicrobial drugs are divided into categories based on which of these metabolic targets they affect. These categories are? (see slide 27)

1. Inhibitions of cell wall synthesis\ 2. Inhibition of nucleic acid (RNA and DNA) structure and function 3. Inhibition of protein synthesis 4. Interference with cytoplasmic membrane structure or function 5. Inhibition of folic and acid synthesis

Once therapy has begun, it is important to observe the patient's clinical response, because the iN VITRO activity of the drug is not always correlated with its IN VIVO effect. When antimicrobial treatment fails, the failure is due to one or more of the following:

1. The inability of the drug to diffuse into that body compartment (brain, joints, skin) 2. Resistant microbes in the infection that didn't make it into the sample collected for testing 3. An infection caused by more than one pathogen (mixed), some of which are resistant to the drug

Before antimicrobial therapy begins, three factors should be known:

1. The microorganism causing the infection 2. The microorganism's susceptibility (or sensitivity) to various drugs 3. The medical condition of the patient

Whether antibiotics are present or not, microbes become newly resistant to a drug after one of the following two events occur:

1. spontaneous mutations in critical chromosomal genes 2. acquisition of entire new genes or sets of genes via HORIZONTAL TRANSFER from other species

Often, the quest for new antimicrobial strategies focuses on finding new targets in the bacterial cell and custom-designing drugs that aim for them. There are many interesting new strategies that have not yet resulted in a marketable drug-for example:

1. targeting iron-scavenging capabilities of bacteria 2. using RNA interference strategies 3. mimicking molecules called defense peptides 4. using bacteriophages

NATURE is a prolific producer of antimicrobial drugs. ANTIBIOTICS, after all, are natural metabolic products of?

AEROBIC bacteria and fungi ***Produced to inhibit the growth of competing microbes in the same habitat

This reaction occurs because the drug acts as an?

ANTIGEN (a foreign material capable of stimulating the immune system) an stimulates an allergic response

The goal of ANTIMICROBIAL CHEMOTHERAPY is deceptively simple:

Administer a drug to an infected person, which destroys the infective agent without harming the host's cells

What are Synthetic Drugs?

Drugs produced ENTIRELY BY CHEMICALS

What are Semisynthetic Drugs?

Drugs that are CHEMICALLY MODIFIED IN THE LABORATORY after being isolate from natural sources

Drugs most often adversely affect the following organs:

Liver (HEPATOXIC), Kidney (NEPHROTOXIC), Gastrointestinal Tract, Cardiovascular System and blood forming tissues (HEMOTOXIC), Nervous System (NEUROTOXIC), Respiratory Tract, Skin, Bones, and Teeth

A widely used amoebicide, _________ is effective in treating mild and severe intestinal infections and hepatic disease caused by Entamoeba

Metronidazole

____________ has bee the Principal treatment of malaria for hundreds of years

Quinine

Because drug toxicity to the host is of concern, it is best to choose he one with HIGH SELECTIVE TOXICITY and LOW HUMAN TOXICITY. The Therapeutic Index (TI) is defined as the?

Ratio of the dose of the drug that is toxic to humans as compared to its minimum effective (therapeutic) dose ***The drug with the highest therapeutic index has the widest margin of safety (see slide 17)

In actuality, this goal is rather difficult to achieve, because many factors must be taken into account. Here are those factors:

The ideal drug should be easy to administer, yet be able to reach the infectious agent, while being nontoxic to the host; and remain active in the body as long as needed, yet be safely and easily broken down and excreted

What is antimicrobial chemotherapy?

The use of chemotherapeutic drugs to CONTROL infection

One of the most frequent drug reactions is?

allergy

One unfortunate outcome of the use of antimicrobials is the development of microbial DRUG RESISTANCE, which is?

an adaptive response in which microorganisms begin to tolerate an amount of drug that would ordinarily be inhibitory

Among the most toxic to human cells are drugs that act upon a structure common to?

both the ineffective agent and the host cell, such as the cytoplasmic membrane

Resistance (R) Factors are transferred through?

conjugation, transformation, or transduction

The major side effects of drugs fall into what 3 categories?

direct damage to tissues through toxicity, allergic reactions, and disruption in the balance of normal microbial biota ***the damage incurred by antimicrobial drugs can be short-term and reversible or permanent, and it ranges in severity from cosmetic to lethal.

Most normal, healthy body surfaces, such s the skin, large intestine, outer opening of the urogenital tract, and oral cavity, provide numerous habitats for a virtual "garden" or microorganisms. These normal colonists, or residents, called the BIOTA or microbiota, consists mostly of?

harmless or beneficial bacteria, but a small number can potentially be pathogens

During an infection, the microbe is living in or on a host; therefore, the drug is administered to the?

host though its target us the microbe **therefore the effect of the drug on the host must always be considered

Patients must be asked about other drugs they are taking because incompatibilities can result in?

increased toxicity or failure of one or more of the drugs

The property of drug resistance can be?

intrinsic as well as acquired

Biofilm inhabitants behave differently than their free-living counterparts. One of the major ways they differ- at least from a medical perspective is that they are often unaffected by the?

same antimicrobials that work against them when they are free living ****Bacteria in biofilms express a different phenotype and have different antibiotic susceptibility profiles than free-living bacteria

RNA INTERFERENCE refers to small pieces or RNA that regulate gene expressions. This is being exploited in attempts to?

shut down the metabolism of pathogenic microbes

Drug resistance that is found on chromosomes usually results from?

spontaneous random mutations in bacterial populations

This response can be provoked by the intact drug molecule or by?

substances that develop from the body's metabolic alteration of the drug ***in the case of penicillin, for instance, it is not the penicillin molecule itself that causes the allergic response but a product, benzylpenicillolyl.

If a BROAD SPECTRUM antimicrobial is introduced into a host to treat infection, it will destroy microbes regardless of their roles as normal biota, affecting not only the targeted infectious agent but also many others in sites far removed from the original infection. When this therapy destroys beneficial resident species, other microbes that were once in small numbers begin to overgrow and cause disease. This complication is called? (see slide 72)

superinfection

Contrary to popular belief, antibiotic resistance is an ancient phenomenon. In 2012, 93 bacterial species were discovered in a cave in New Mexico that had been cut off from the surface for millions of years. Most of these species were found to have resistance to multiple antibiotics- antibiotics naturally produced from fungi and bacteria, resistance to them has been a?

survival strategy for other microbes for as long as the microbes have been around

Any large population of microbes is likely to contain a few individual cells that are already drug resistant because of prior mutations or transfer of plasmids. While we now know that many things can cause these "odd balls" to start overtaking the population, one of the most reliable ways to make this happen is for the correct antibiotic to be present. Sensitive individuals are inhibited or destroyed and resistant forms will?

survive and proliferate ***during subsequent population growth, offspring of these resistant microbes will inherit this drug resistance

Penicillins have a low toxicity and few direct effects on human cells because human cells lack?

the chemical PEPTIDOGLYCAN and are thus unaffected by this action of the antibiotic

The physician must also take a careful history of the patient to discover any preexisting medical conditions that will influence the activity of the drug or the response of the drug and drugs related to it. Underlying liver or kidney disease will ordinarily require changing the drug therapy, because...? (see slide 18)

these organs play such an important part in metabolizing or excreting the drug **** Infants, the elderly, and pregnant women require special precautions. For example, age can diminish gastrointestinal absorption and organ function, and most antimicrobial drugs cross the placenta and could affect fetal development