Chapter 20: Antimicrobial Medications

Broad-spectrum antimicrobials

Affect a wide range of bacteria. Important for treating acute life-threatening diseases when immediate antimicrobial therapy is essential and there is no time to culture and identify the pathogen. However, by affecting a wide range of microbes they disrupt the normal microbiota that play an important role in excluding pathogens which can leave the patient predisposed to other infections.

Vancomycin-resistant enterococci (VRE)

Enterococci that are resistant to vancomycin, the drug that is usually reserved as a last resort for treating life-threatening infections caused by Gram-positive organisms resistant to all B-lactam drugs. This vancomycin resistance that is encoded on a plasmid can be transferred to other organisms

Chemotherapeutic agents

chemicals used to treat disease

Paul Ehrlich

A German physician and bacteriologist. Observed that certain dyes stain bacterial cells but not animal cells, leading him to search for a "magic bullet" that would kill a microbial pathogen without harming the human host. They tested arsenic that could help treat syphilis caused by Treponema pallidum, developed salvarsan. Ehrlich's discovery proved that some chemicals could selectively kill microbes. This was the first documented example of a chemical used successfully as an antimicrobial medication

Emerging Antimicrobial Resistance: Staphylococcus aureus

A common cause of healthcare-associated infections. Becoming increasingly resistant to antimicrobials. Most strains are now resistant to penicillin due to their acquisition of a gene encoding penicillinase.

Acyclovir

A drug use to treat herpesvirus infections. It causes little harm to uninfected cells because normal cellular enzymes do not convert the drug into a nucleotide analog. A virally encoded enzyme, only present in cells infectd by herpesvirus such as herpes simplex virus (HSV) and varicella-zoster virus (VZV), does this

Azoles

A family of chemically synthesized drugs, some of which have antifungal activity. Two classes: Imidazoles and triazoles. Both classes inhibit ergosterol synthesis, resulting in defective fungal membranes that leak cytoplasmic contents. Fluconazole and voriconazole (triazoles) are increasingly being used to treat systemic fungal infections. Ketoconazole (imidazole) is used systemically but has more severe side effects. Other imidazoles including miconazole and clotrimazole are commonly used in non-prescription creams, ointments, and suppositories to treat vaginal yeast infections. They are also applied to the skin to treat dermatophyte infections.

Polyenes

A group of antibiotics produced by certain species of streptomyces that bind to ergosol disrupting the fungal membrane, killing the cell by allowing its cytoplasmic contents to leak out. Polyenes are quite toxic to humans, limiting their systemic use to life-threatening infections. Amphotericin B causes severe side effects, but it is the most effective drug for treating certain systemic infections. Lipid based emulsions are less toxic but more expensive. Nystatin is too toxic to be given systemically, but is used topically

Flucytosine

A synthetic derivative of cytosine. Enzymes within infecting yeast cells convert flucytosine to 5-fluorouracil, which inhibits an enzyme required for nucleic acid synthesis. Unfortunately, resistant mutations are common, therefore, flucytosine is used mostly in combination with amphotericin B or as an alternative drug for patients with systemic yeast infections who can't tolerate amphotericin B. Flucytosine is not effective against molds

Narrow-spectrum antimicrobials

Affect a limited range of bacteria. Their use requires that the pathogen be identified and its antimicrobial susceptibility tested, but they cause less disruption to the normal microbiota

Semisynthetic

An antibiotic that is chemically altered after beeing extracted and purified to give it new characteristics such as increased stability

Mechanisms of acquired resistance: Alteration in the target molecule

Antimicrobial drugs generally act by recognizing and binding to trget molecules in a bacterium, interfering with their function. Minor structural changes in the target can prevent the drug from binding. Modification in teh PBPs prevent B-lactam drugs from binding to them. A change in rRNA, the target for macrolides, prevent them from interfering with ribosome function

Antibiotics

Antimicrobial drugs naturally produced by microorganisms. Penicillin G, the most suitable penicillium culture for treating infections was the first antibiotic. Hundreds of tons and many millions of dollars' worth of antibiotics are now produced each year

Spontaneous Mutation

As cells replicate spontaneous mutations occasionally happen. The few mutations that occur can have a significant effect on the antimicrobial resistance of a bacterial population. Acquired resistance to streptomycin is good example of the consequence of spontaneous mutation. A single base-pair change in the gene encoding a ribosomal protein alters the target enough to make the cell streptomycin-resistant. When an antimicrobial drug has several different targets or multiple binding sites on a single target, resistance through spontaneous mutation is less likely to occur because several different mutations would be required to prevent binding of the drug. Newer aminoglycosides ind to several sites on the ribosome making spontaneous mutation resistance unlikely.

Aminoglycosides

Bactericidal drugs that irreversibly bind to the 30S ribosomal subunit, causing it to distort and malfunction. This blocks the initiation of translation and causes misreading of mRNA by ribosomes that have already passed the initiation step. Generally not effective against anaerobes, enterococci and streptococci, because they enter bacterial cells by an active transport process that requires respiratory metabolism. To extend their spectrum of activity, the aminoglycosides are sometimes used in a synergistic combination. with a B-lactam drug, the B-lactam drug interferes with cell wall synthesis which allows the aminoglycoside to enter cells that would otherwise be resistant. Streptomycin, tobramycin, gentamicin and amikacin. Can cause severe side effects including hearing loss and kidney damage; generally used only when alternative aren't available. Tobramycin administered through inhalation rather than injection makes treatment of lung infections in cystic fibrosis patients caused by P. aeruginosa safer and more effective. Neomycin is too toxic for systemic use but it is a common ingredient in non-prescription topical ointments

Mechanisms of Action Antifungal Drugs: Interfere with nucleic Acid synthesis

Because nucleic acid synthesis is common in all eukaryotic cells it is a poor target for antifungal drugs. The drug Flucytosine, however, is taken up by yeast cells and then converted by yeast enzymes to an active, inhibitory form

Lincosamides

Bind to the 50S subunit and prevent continuation of translation. bacteriostatic. Bacteriostatic. Inhibit a variety of Gram-negative and Gram-positive bacteria. Particularly useful for treating infections resulting form intestinal perforation because they inhibit bacteroides fragilis, a member of the normal intestinal microbiota that is frequently resistant to other antimicrobials. The risk of developing Clostridium difficile-associated disease is greater for people taking lincosamides than some other anitimicrobials because most C. difficile strains are resistant to the lincosamides. Most commonly used lincosamide is clindamycin

Oxazolidinones

Bind to the 50S subunit, interfering with the initiation of translation. Bacteriostatic against a variety of Gram-positive bacteria and are useful in treating infections caused by bacteria that are resistant to B-lactam drugs and vancomycin. Linezolid is an example.

Chloramphenicol

Binds to the 50S ribosomal subunit, preventing peptide bonds from being formed and blocking translation. Bacteriostatic. Active against a wide range of bacteria, generally only used as a last resort for life-threatening infections in order to avoid a rare but lethal side effect: aplastic anemia, can occur in response to even a small amount of chloramphenicol, is characterized by the inability of the body to form white and red blood cells

Rifamycins

Block prokaryotic RNA polymerase from initiating transcription. Rifampin, the most widely used rifamycin, is bactericidal against many gram-positive and some gram-negative bacteria as well as mycobacterium. Primarily used to treat tuberculosis and Hansen's disease and to prevent meningitis in people who have been exposed to Neisseria meningitidis. In some patients, a reddish-orange pigment appears in urine and tears. Resistance to the drug develops rapidly due to a mutation in the gene that encodes RNA polymerase

Vancomycin

Blocks peptidoglycan synthesis by binding to the peptide side chain of NAM molecules being assembled to form glycan chains. Weakens the cell wall and causes lysis. The drug is poorly absorbed from the intestinal tract so it must be administered IV except when used to treat intestinal infections. Very important for treating infections caused by gram-positive bacteria resistant to B-lactam drugs. Also used to treat severe cases of Clostridium difficile associated disease that do not respond to metronidazole. Vanco is referred to as the last resort antibiotic because it is reserved for organisms resistant to all other options. New alternatives have been developed but vanco is still the drug of choice for treating most infections caused by Gram-positive bacteria resistant to other drugs. Doesn't cross the outer membrane of gram-negative bacteria, so they are intrinsically resistant. Acquired resistance to vanco is an increasing problem, most often due to a change in the peptide side chain of the NAM molecule that prevents vancomycin from binding.

Other B-lactam antibiotics

Cabapenems and monobactams. Are resistant to most B-lactamases. Carbapenems are effective against a wide range of Gram negative and positive bacteria; four types are available-imipenem, meropenem, ertapenem, and doripenem. Imipenem is destroyed by a kidney enzyme and is therfore given in combination with a drug that inhibits that enzyme. Bacteria that produce carbapenemases are resistant. The only monobactam used therapeutically, aztreonam, is primarily effective against members of the family Enterobacteriacea, which are gram-negative rods. Aztreonam has a slightly different structure than other B-lactam drugs, can be given to patients who are allergic to penicillin. Bacteria that produce ESBLs are resistant to aztreonam.

intrinsic (innate) resistance

Certain bacteria are inherently resistant to the effect of some drugs. I.e. mycoplasma lack a cell wall, making them resistant to penicillin and any other drug that interferes with peptidoglycan synthesis. Many gram-negative bacteria are also intrinsically resistant to certain drugs because the lipid bilayer of their outer membrane prevents the drug from entering.

Penicillins + B-lactamse inhibitor

Combination of agents. The B-lactamase inhibitor interferes with the activity of some types of B-lactamases, protecting the penicillin against enzymatic destruction. Augmentin, a combination of amoxicillin and clavulanic acid.

Nucleoside Analogs

Compounds similar in structure to a nucleoside. These analogs can be phosphorylated in vivo by a virally encoded or normal cellular enzyme to form a nucleotide analog, a chemical structurally similar to the nucleotides of DNA and RNA. When a nucleotide analog is incorporated into a growing nucleotide chain, it sometimes prevents additional nucleotides from being added. In other cases the analog results in a defective strand with altered base-pairing properties. Most nucleoside analogs are reserve for severe infections because of their significant side effects

Non-nucleoside Polymerase inhibitors

Compounds that inhibit the activity of viral polymerases by binding to a site other than the nucleotide-binding site. Foscarnet, is used to treat infections caused by ganciclovir-resistant CMV and acyclovir-resistant HSV

Antimicrobials that interfere with Cell membrane integrity

Daptomycin inserts into bacterial cytoplasmic membranes and is used to treat infections caused by gram-positive bacteria resistant to other drugs. Not effective against gram-neg bacteria because it can't penetrate the outer membrane. Polymyxin B (common ingredient in first-aid skin ointments) binds to membranes of gram-negative cells. Also bind to eukaryotic cells which limits their use to topical applications

The cephalosporins

Derived from an antibiotic produced by the fungus Acremonium cephalosporium. Generally included in the cephalosporin family is a closely related group of antibiotics made by filamentous bacteria related to Streptomyces. Cephalosporin's chemical structure makes them resistant to inactivation by certain B-lactamases. Some are not effective against gram-positive bacteria because the drugs have a low affinity for their PBPs. Cephalosporins have been modified to up to fourth generation versions including cephalexin and cephradine (first generation), ceflacor and cefprozil (second generation), cefixime and ceftibuten (third generation) and cefepime (fourth generation). Later generations are more effective against gram-negative bacteria and less susceptible to destruction by B-lactamases.

Combination therapy

Drugs such as streptomycin for which a single point mutation causes resistance are sometimes used in combination with one or more drugs. If any spontaneously develops resistance to one drug, another will kill it. Effective because the chance of a cell developing resistance to two drugs simultaneously is extremely low.

Bacteriostatic

Drugs that inhibit bacterial growth are bacteriostatic. A person taking these drugs must rely on their body's defenses to kill or eliminate the pathogen after its growth has been stopped. Sulfa drugs, frequently prescribed for UTIs prevent bacteria in the bladder from growing, so that urination can more effectively eliminate them.

Slowing emergence and spread of antimicrobial resistance: Interfere with Viral unoating

Drugs that interfere with the uncoating step prevent viral replication. Amantadine and rimantadine do this. They block influenza A virus. They both prevent or reduce the severity of the diseases, but viral strains develop resistance easily, limiting their usefulness

Penicillin-binding proteins (PBPs)

Enzymes that catalyze the formation of peptide bridges between adjacent glycan strands. THey bind penicillin and were initially discovered during experiments to study the effects of the medication

Metronidazole

Flagyl interferes with DNA synthesis and function, but only in anaerobic microorganisms. The selective toxicity is due to the fact that anaerobic metabolism is required to convert the medication to its active form. The active form binds DNA, interfering with synthesis and causing damaging breaks. Used to treat bacterial vaginosis and Clostridium difficile-associated disease

Mechanisms of Action Antifungal Drugs: Interfere with Cell Wall Synthesis

Fungal cell walls contain some components not produced by animal cells. Echinocandins, a family of drugs, interfere with synthesis of cell wall component B-1,2 glucan, causing fungal cells to burst. Caspofungin, the first member to be approved, is used to treat candida infections as well as invasive aspergillosis that resists other treatments

Other nucleoside analogs

Ganiclovir, which is used to treat life or sight-threatening cytomegalovirus (CMV) infections in immunocompromised patients. Ribavirin, which is used to treat respiratory syncytial virus infections (RSV) in newborns. Nucloside analogs used to treat HIV infections interfere with the activity of reverse transcriptase and are called nucleoside reverse transcriptase inhibitor (NRTIs). The virus rapidly develops mutational resistance to these drugs, which is why they are often used in combination with other anti-HIVdrugs. NRTIs include zidovudine (AZT), didanosine (ddI), and lamivudine (3TC). Two of these are often used in combination for HIV therapy

Gene transfer: R plasmids

Genes encoding resistance to antimicrobial drugs can spread to different strains species and even genera, most commonly through conjugative transfer of these plasmids. They often carry several different resistance genes, each one encoding resistance to a specific antimicrobial drug. When an organism acquires an R plasmid, it becomes resistant to several different medications simultaneously.

Slowing emergence and spread of antimicrobial resistance: An educated public

Greater effort must be made to educate people about the role and limitations of antibiotics. People need to understand they are not effective against viruses. Taking antibiotics will not cure the common cold or any other viral illness. Many people mistakenly believe that antibiotics are effective against viruses and seek prescriptions to cure viral infections This selects for antibiotic-resistant bacteria in the normal microbiota which can serve as a reservoir for R plasmids and transfer their resistance genes to an infecting pathogen

Mechanisms of Action of Antiviral Drugs: Prevent Viral Entry

Group of drugs effective against HIV prevent the virus from entering host cells. Enfuvirtide does this by binding to an HIV protein that promotes fusion of the viral envelope with the cell membrane. Maraviroc blocks the HIV co-receptor CCR5

Extened-spectrum penicillins

Have greater activity against Pseudomonas species-Gram-negative bacteria that are unaffected by many antimicrobial drugs. This group of penicillins has less activity against Gram-positive bacteria. They are destroyed by many B-lactamases. Extended spectrum penicillins include ticarcillin and piperacillin

Alexander Flemming

He was working with cultures of Staph aureus when he noticed that colonies growing near a contaminating mold looked as if they were dissolving. He recognized that the mold might be secreting a substance that killed bacteria and studied it more carefully. The mold was a species of Penicillium, he found it was indeed producing a bacteria-killing substance; he called it penicillin. Fleming wasn't able to purify penicillin but he showed that it was effective in killing many different bacterial species and did not cause adverse effects when injected into rabbits and mice. He eventually abandoned his study of penicillin out of discouragement from not being able to purify it.

Vancomycin-intermediate S. aureus (VISA) and vancomycin resistant S. aureus (VRSA)

Healthcare associated (HA-MRSA) are generally resistant to a wide range of antimicrobial medications, so they are generally treated with vancomycin, but a few hospitals have reported isolates that aren't susceptible to normal levels of vancomycin. Strict hospital guidelines designated to immediately halt the spread of these strains have been successful.

Second-line drugs

In combination therapy these drugs are used for strains resistant to the first-line drugs; either less effective or have greater risk of toxicity.

Gene transfer

In some cases, resistance genes originate through spontaneous mutation of common bacterial genes, such as one encoding the target of the drug. In other cases, the genes may have originated from the soil microbes that naturally produce that antibiotic. A gene coding for an enzyme that chemically modifies an aminoglycoside likely originated from the Streptomyces species that produces the drug

Neuraminidase Inhibitors

Inhibit neuraminidase, an enzyme encoded by influenza virus. This enzyme is important for the release of viral particles from infected cells. Two neuraminidase inhibitors are currently available-zanamivir, which is administered by inhalation, and oseltamivir, which is taken orally. Both shorten the infection when taken within two days of the onset of symptoms

Non-nucleoside Reverse Transcriptas Inhibitors (NNRTIs)

Inhibit the activity of reverse transcriptase by binding to a site other than the nucleotide-binding site. Are often used in combination with nucleoside analogs to treat HIV infections. Medication include, Nevirapine, delavirdine and efavirenz

Bacitracin

Inhibits cell wall biosynthesis by interfering with the transport of peptidoglycan precursors across the cytoplasmic membrane. Its toxicity limits its use to topical applications however it is a common ingredient in non-prescription first-aid ointments.

Trimethoprim

Inhibits the bacterial enzymethat catalyzes a metabolic step following the one inhibited by sulfonamides. The drug has little effect on the enzyme's counterpart in human cells. The competition of trimethoprim and a sulfonamide has a synergistic effect and tehy are often used together to treat UTIs. The most common mechanism of resistance is a plasmid-encoded alternative enzyme that has a lower affinity for the drug. The genes encoding resistance to trimethoprim and sulfonamide are often carried on the same plasmid

Slowing emergence and spread of antimicrobial resistance: Prevent Genome integratoion

Integrase inhibitors offer a new option for treating HIV infections. They inhibit the HIV-encoded enzyme integrase, preventing the virus from inserting hte DNA copy of its genome into the at of the host cell. Raltegravir is the first approved dug of this class

Emerging Antimicrobial Resistance: Enterobacteriaceae

Intrinsically resistant to many antimicrobial medications because their outer membrane prevents the drugs from entering cells. Some enterics developed the ability to produce a B-lactamase, allowing the strains to resist the effects of ampicillin and other penicillins. Some strains then developed the ability to produce extended-spectrum B-lactamases (ESBLs) making them resistant to most cephalosporins and aztreonam as well.

Development of new generation Drugs

It was discovered that certain antimicrobial drugs chemical structures could be altered. Penicillin G, which is mainly active against gram positive bacteria is altered to produce ampicillin, a drug that kills a variety of gram-negative species as well. Methicillin, which is less susceptible to enzymes used by some bacteria to destroy penicillin, was also created by altering penicillin. A variety of penicillin-like medications exist today, making up the family of penicillins. Other antimicrobial drugs have also been altered to give them new characteristics

Extensively drug-resistant M. tuberculosis (XDR-TB)

M. tuerculosis strains resistant to isoniazid and rifampin, plus three or more second-line drugs

Selective Toxicity

Medically useful antimicrobial drugs exhibit this, causing greater harm to microbes than to the human host. This is done by interfering with essential structures or biochemical processes that are common in microbes but not human cells.

Antiviral Drugs

Medications that interfere with viral replication. The relatively few options available are generally only effective against a specific type of virus, and none can eliminate latent viral infections

The penicillins

Members of the penicillin family share a common basic structure. The side chain of the structure has been chemically modifies to create penicillin derivatives, each with unique characteristics.

Mechanism of Action of Antiprotozoan and Antihelminthic Drugs

Most antiparasitic drugs probably interfere with biosynthetic pathways of protozoan parasites or the neuromuscular function of worms. Compared with antibacterial, antifungal and antiviral drugs, little research and development goes into these drugs, because most parasitic diseases are concentrated in the poorer areas of the world where people cannot afford to spend money on expensive medications.

Multidrug-resistant M. tuberculosis (MDR-TB)

Mycobacterium tuberculosis strains that are resistant to isoniazid and rifampin, the two favored drugs for tuberculosis treatment. TO prevent emergence of these strains, some cities are using directly observed therapy. Patients are observed taking their drugs, making sure they are complying with their antimicrobial treatment

Slowing emergence and spread of antimicrobial resistance: Patients

Need to carefully follow instructions that accompany their prescriptions, even if inconvenient. It is essential to maintain adequate blood levels of the antimicrobial for a specific time period. When a patient skips a scheduled dose the blood level of the drug may not remain high enough to inhibit the growth of the least-sensitive members of the population. They then have a chance to grow and give rise to a less sensitive population, resulting in failure of treatment and rise of more resistant bacteria.

Slowing emergence and spread of antimicrobial resistance: Physicians and other healthcare workers

Need to increase their efforts to identify the cause of a given infection and, if appropriate, prescribe suitable antimicrobials. Must also educate patients about proper use of prescribed drugs in order to increase compliance. May be more expensive in short term but will ultimately save lives and money

Glycylcyclines

New class of antibacterial drugs related to the tetracyclines. Have the same mechanism of action and effect as the tetracyclines but a wider spectrum of activity. Effective against many bacteria that have acquired resistance to the tetracyclines. Tigecycline is the only currently approved example

Methicillin-resistant Staphylococcus aureus

New strains of S. aureus have emerged that not only produce penicillinase, but also have penicillin binding proteins with low affinity for all B-lactam drugs. These strains are resistant to methicillin as well as all other B-lactam drugs. Community acquired (CA-MRSA) strains are currently susceptible to antibiotics other than B-lactam drugs

Suppression of the Normal Microbiota

Normal microbiota is important in excluding pathogens. When its composition is altered, when a person takes antimicrobials, pathogens that usually can't compete can multiply to high numbers. Broad-spectrum antibiotics taken orally can cause a patient to develop life-threatening antibiotic-associated colitis, caused by toxin-producing strains of Clostridium difficile which can't normally establish itself in the intestines because of competition from other bacteria. The antimicrobials inhibit or kill some of the normal intestinal microbiota and C. difficile can sometimes flourish and cause intestinal damage, resulting in Clostridium difficile-associated disease

Mechanisms of Action Antifungal Drugs: Interfere with Cell Division

One antifungal drug, griseofulvin, targets cell division. It interferes with the action of tubulin, a structure required for nuclear division. Tubulin is a part of all eukaryotic cells so griseofulvin's selective toxicity may be due to its greater uptake by fungal cells. When taken orally for months it is absorbed and eventually concentrated in the dead keratinized layers of the skin. Fungi that then invade keratin-containing structures such as skin and nails take up the drug, which prevents them from multiplying. Griseofulvin is only active against fungi that invade keratinized cells and is used to treat skin and nail infetions

Tissue Distribution, metabolism and excretion of the drug

Only some drugs cross from the blood into the cerebrospinal fluid, an important factor in treating meningitis. Drugs that are unstable at low pH are destroyed by stomach acid when swallowed, they must be administered through intravenous or intramuscular injection. The rate of elimination (the half-life) of a drug is the time it takes for the serum concentration to decrease by 50% dictating the frequency of doses required to maintain an effective level in the body. Penicillin V has a short half-life and must be taken four times a day, whereas azithromycin has a half-life of over 24 hours and is taken once a day or less. Patients who have kidney or liver dysfunction excrete or metabolize drugs more slowly so their dosages must be adjusted accordingly to toxicity levels.

Emerging Antimicrobial Resistance: Enterococci

Part of the normal intestinal microbiota and a common cause of healthcare-associated infections. Are intrinsically less susceptible to many common antimicrobials. Their penicillin-binding proteins have low affinity for certain B-lactam antibiotics. Many enterococci have R plasmids.

B (beta)-lactam drugs

Penicillins and cephalosporins are members of this group of antimicrobial medications. This group, which also includes the monobactams and carbapenems, all have a shared chemical structure, the B-lactam ring. These drugs competitively inhibit a group of enzymes that catalyze the formation of peptide bridges between adjacent glycan strands, an essential step in the final stages of peptidoglycan synthesis. This disruption of cell wall synthesis weakens the wall and causes the cell to lyse. These drugs are bactericidal only against growing bacteria because they continuously synthesize peptidoglycan. Different B-lactam drugs vary in their spectrum of activity. One reason for this is difference in the cell wall structure of bacteria. Peptidoglycan of gram-positive organisms is exposed to the outside environment, so the B-lactam drugs can directly contact the enzymes that synthesize the molecule. The outer membrane of Gram-negative bacteria prevents the drugs from accessing the target. The PBPs of Gram-positive bacteria differ somewhat from those of gram-negative bacteria and the PBPs of obligate anaerobes form those of aerobes. Various PBPs have different affinities for the B-lactam drugs. Differences can even exist among related organisms such as gram-positive cocci

Mechanisms of acquired resistance: Decreased uptake of the drug

Porin proteins in the outer membrane of Gram-negative bacteria selectively permits small hydrophobic molecules to enter a cell. Changes in these proteins can prevent certain drugs from entering the cell. By stopping entry the organism avoids the drugs' effects

First-line drugs

Preferred for use against Mycobacterium tuberculosis and related species because they are the most effective and least toxic. Generally given in combination of two or more to patients who have active tuberculosis disease. Combination therapy decreases the chance that resistant mutants will develop. Some specifically target the unique cell wall that characterized the mycobacteria. Isoniazid inhibits the synthesis of mycolic acids, a primary component of the cell wall. Ethambutol inhibits enzymes required for synthesis of other mycobacterial cell wall components. Mechanism of pyrazinamide is unknown. Other first-line drugs include rifampin and streptomycin

Acquired resistance

Previously sensitive organisms dvelop this resistance through spontaneous mutation or horizontal gene transfer

Streptogramins

Quinupristin and dalfopristin are administered together in a medication called synercid. Act as a synergistic combination, binding to two different sites on the 50S ribosomal subunit and inhibiting distinct steps of translation. Individually each drug is bacteriostatic but together they are bactericidal. Effective against a variety of gram-positive bacteria including some that are resistant to B-lactam drugs and vancomycin

Tetracyclines

Reversibly bind to the 30S subunit blocking attachment of tRNA, preventing translation from continuing. These bacteriostatic drugs are actively transported into prokaryotic but not animal cells, which effective concentrates them inside bacteria. This in part accounts for their selective toxicity. Tetracyclines are effective against certain gram-positive and gram-negative bacteria. Derivatives such as doxycycline have a longer half-life allowing less frequent doses. Tetracycline resistance is due to a decrease in their accumulation by the bacterial cell by decreased uptake or increased secretion

Macrolides

Reversibly bind to the 50S subunit and prevent the continuation of translation. Often serve as the drug of choice for people who are allergic to penicillin. Bacteriostatic against many gram-positive bacteria as well as the most common causes of atypical pneumonia (walking pneumonia). Not effective against enterobacteriacae because they don't pass through the outer membrane. Erythromycin, clarithromycin and azithromycin. Clarithromycin and azithromycin have a longer half-life than erythromycin so they can be taken less frequently. Resistance can occur through modification of the ribosomal RNA target, production of an enzyme that chemically modifies the drug, and alterations that result in decreased drug uptake

Toxic effects

Several antimicrobials are toxic at high concentrations or cause adverse reactions. Aminoglycosides such as streptomycin can damage kidneys, impair the sense of balance and even cause irreversible deafness. Patients who take these drugs must be monitored closely because of the low therapeutic index. Some antimicrobials have life threatening effects so sever that they are reserved only for life-threatening conditions. Chloramphenicol causes the potentially lethal condition aplastic anemia, in which the body is unable to make white and red blood cells, therefore this drug is usually only used when no alternatives are available

Mechanisms of acquired resistance: Drug-inactivating enzymes

Some bacteria produce enzymes that chemically modify a specific drug, interfering with its function. Penicillinase destroys penicillin. Chloramphenicol acetyltransferase chemically alters chloramphenicol making it innefective

B-lactamase

Some bacteria resist the effects of certain B-lactam drugs by synthesizing one of these enzymes that breaks the critical B-lactam ring, destroying the activity of the antibiotic. There are various B-lactamases that differ in the range of drugs they destroy. Penicillinase is a B-lactamase that inactivates only members of the penicillin family. Extended-spectrum B-lactamases (ESBLs) inactivate a wide variety of B-lactam drugs, including both the penicillins and cephalosporins. Gram-negative bacteria produce a much more extensive array of B-lactamases than gram-positive organisms can.

Allergic Reactions

Some people develop allergies to antimicrobial drugs. Penicillin allergy usually results in a fever or rash but can abruptly cause life-threatening anaphylactic shock. People who have allergic reactions to these or any drugs must alert their physician and pharmacist so a different drug can be prescribed. They should wear a bracelet or necklace that records that information in case of emergency.

Combinations of antimicrobials

Sometimes used to treat infections but must be chosen carefully because some drugs can counteract others. Bacteriostatic drugs interfere with the actions of drugs that kill only actively dividing cells. Counteracting combinations like this are antagonistic. Combinations where one drug enhances the activity of another are synergistic. Combinations that are neither synergistic nor antagonistic are additive

Selman Waksman

Soon after the discovery of penicillin, he isolated Streptomyces griseus from soil. It produced an antibiotic he called streptomycin. Discovery that molds and bacteria could produce antibiotics prompted researchers to begin screening different microbial strains for antibiotic production. Pharmaceutical companies to this day examine soil samples from around the world for microbes that produce novel antibiotics

Carbapenem-resistant enterobacteriaceae (CRE)

Strains of Enterobacteriaceae that are resistant to nearly all available antimicrobial drugs. Produce an enzyme that inactivates cabapenems, a group of drugs considered a last resort for treating infetions caused by ESBL-producing bacteria

Ernst Chain and Howard Florey

Successfully purified penicillin. In 1941 the drug was tested for the first time on a police officer with a life-threatening Staph aureus infection. He improved within 24 hours and his illness seemed under control, but the supply of purified penicillin ran out and the man eventually died of infection

Sulfa drugs

Sulfonamides inhibit growth of many gram-positive and negative bacteria. Structurally similar to para-aminobenzoic acid (PABA), a substrate in the pathway for folate biosynthesis. The enzyme that normally binds PABA binds sulfa drugs instead, competitive inhibition. Human cells lack this enzyme providing the basis for the selective toxicity of the sulfonamides. Resistance is often due to the acquisition of a plasmid-encoded enzyme that has a lower affinity for the drug.

Fluoroquinolones

Synthetic drugs that inhibit one or more groups of enzymes called topoisomerases, which maintain the supercoiling of DNA within the bacterial cell. One type of topoisomerase, DNA gyrase, breaks and rejoins strands to relieve the strain caused by the localized unwinding of DNA during replication and transcription. Inhibition of this enzyme prevents these essential processes. Bactericidal against a wide variety of both gram-positive and gram-negative bacteria. Ciprofloxacin and moxifloxacin. Acquired resistance is commonly due to an alteration in the DNA gyrase target.

Emerging Antimicrobial Resistance: Streptococcus pneumoniae

The leading cause of pneumonia in adults. Some isolates are now resistant to penicillin due to changes in the chromosomal genes coding for the targets of penicillin-PBPs. The modified targets have lower affinities for the drug. The nucleotide changes appear to be due to the acquisition of chromosomal DNA from other Streptococcus species. S. pneumoniae can acquire DNA through DNA-mediated transformation.

Minimum inhibitory concentration

The lowest concentration of a specific antimicrobial drug needed to prevent the growth of a given bacterial strain in vitro. Determined by growing the test strain in broth cultures containing different concentrations of the antimicrobial. Microbes that have an MIC on the borderline between susceptible (treatable) and resistant (untreatable) are called intermediate

Minimum bactericidal concentration (MBC)

The lowest concentration of a specific antimicrobial drug that kills 99.9% of cells of a given bacterial strain in vitro. Determined by finding out how many live organisms remain in tubes from the MIC test that showed no growth. A small sample from each of those tubes is transferred to a plate containing an antibiotic free agar medium. If a sample gives rise to no colonies, then no cells survived that particular drug concentration, indicating that it was bactericidal.

Broad-spectrum penicillins

The modified side chains of these drugs give them a broad spectrum of activity. They retain their activity against penicillin-sensitive gram-positive bacteria, and are also active against gram-negative bacteria. They can be inactivated by many B-lactamases. Include ampicillin and amoxicillin

Natural penicillins

The original penicillins produced naturally by the mold Penicillium chrysogenum. Narrow-spectrum antibiotics, effective against Gram-positive and a few Gram-negative bacteria. Penicillin V is more stable in acid and therefore better absorbed than penicillin G when taken orally. Bacteria that produce penicillinase are resistant to to the natural penicillins

Efflux pumps

The systems that bacteria use to transport damaging compounds out of a cell. When a cell makes more of these pumps, it can eject the drug faster. In addition, structural changes in the pumps can influence the range of drugs that can be pumped out. Resistance that develops by this mechanism might allow an organism to become resistant to several drugs simultaneously making it particularly worrisome

Therapeutic index

The toxicity of a given drug. The lowest dose toxic to the patient divided by the dose typically used for therapy. Antimicrobials that have a high therapeutic index are less toxic, often because the drug acts against a vital biochemical process of microorganisms that does not exist in humans. I.e. Penicillin G, which interferes with bacterial cell wall synthesis, has a very high therapeutic index. Drugs too toxic for systemic use can sometimes be used for topical applications, such as first-aid antibiotic skin ointments

Bactericidal

These drugs kill bacteria. Useful when host defenses cannot be relied on to eliminate pathogens. These drugs are sometimes only inhibitory depending on the concentrations and stage of bacterial growth. The lethal effects of different bactericidal drugs seem to involve the same mechanism, regardless of the drugs target. The antimicrobial-induced cell damage overwhelms the bacterium's ability to detoxify reactive oxygen species, leading to extensive oxidative damage.

Penicillinase-resistant Penicillins

These were developed in response to the problem of penicillinase-producing S. aureus strains. Penicillinase-resistant penicillins indclude methicillin and dicloxacillin. Some penicillinase-producing bacteria acquired the ability to make altered PBPs to which B-lactam drugs no longer bind. S. aureus strains that can do this are called MRSA (methicillin-resistant S. aureus)

Emerging Antimicrobial Resistance: Mycobacterium tuberculosis

Treatment has required a combination of two or more drugs taken for a period of 6 months or more. Unfortunately mycobacterium tuberculosis can become resistant to first-line drugs through spontaneous mutation. Large numbers of bacterial cells are found in an active infection, so it is likely that at least one cell has developed spontaneous resistance to a drug, which is why combination therapy is required. The length of treatment is due to the slow growth of M. tuberculosis. Because many tuberculosis patients skip doses or stop treatment too soon strains of M. tuberculosis develop first-line drug resistance resulting in longer more expensive treatments that are less effective

Diffusion Bioassay

Used to determine concentration of an antimicrobial drug in a fluid specimen. Relies on the same principle as the Kirby-Bauer test, except it is the concentration of the drug not the sensitivity of the organism that is determined. A solid medium uniformly inoculated with a stock organism that is highly susceptible to the drug in question is made. Wells are formed in the agar, standard concentrations of the drug are added to some of the well while others are filled with the body fluid being tested.Zones of inhibition develop during overnight incubation. The sizes of the zones around the patient blood are compared with the ones from the standard drug concentrations.

Kirby-Bauer disc diffusion test

Used to determine the susceptibility of a given bacterial strain to a battery of antimicrobial drugs. Standard concentration of the strain is uniformly spread on the surface of an agar plate. 12 or so discs, containing a known amount of a different drug are placed on the surface of the medium. During incubation, various drugs diffuse outward from the discs forming a concentration gradient around the discs. Regions form around the discs where bacteria were killed or their growth was inhibited. Zone of inhibition reflects the degree of susceptibility of the organism to the drug, and the characteristics of the drug, including its molecular weight and stability as well as the amount in the disc.

Protease inhibitors

Used to treat HIV infections. Inhibit the HIV-encoded enzyme protease, which plays an essential role in the production of infectious viral particles. When HIV replicates, several of its proteins are translated as a polyprotein, a single amino acid chain that must be cleaved by teh protease to release the indiidual proteins. Protease inhibitors-including indinavir, ritonavir, saquinavir, and nelfinavir-differ in dosage and side effects

Nucleoside analog selective toxicity

Virally encoded enzymes are more likely than the host cell polymerases to incorporate a nucleotide analog. More damage is done to the rapidly replicating viral genome than to the host cell genome. The analogs, are only effective against replicating viruses. Herpes virus and HIV can remain latent in cells, so the drugs do not cure these infections; they shorten the active infection.

Gerhard Domagk

almost 25 years after the development of salvarsan by Paul Ehrlich Gerhard Domagk discovered that a red dye called Prontosil could be used to treat streptococcal infections in animals. Prontosil had no effect on streptococci growing in test tubes. It was discovered later that enzymes in the animal's blood split the Prontosil molecule, producing a smaller molecule called sulfanilamide that acted against the infecting streptococci. The discovery of sulfanilamide, the first sulfa drug, was based on luck as well as scientific effort.

Slowing emergence and spread of antimicrobial resistance: Global impacts on the use of antimicrobial drugs

antimicrobial overuse is a worldwide concern. Antimicrobial resistance recognizes no political boundaries. An organism that develops resistance in one country can quickly be transported globally. In developing countries, antimicrobial drugs are available on a non-prescription basis. Many people believe this availability should be restricted or eliminated. The use of antimicrobial drugs in animal feed enhances the growth of animals, but also selects for drug-resistant organisms. Infections caused by drug-resistant Salmonella strains have been linked to animals whose feed was supplemented with those drugs. There is growing pressure worldwide to ban the use of antimicrobial drugs in animal feeds.

Antimicrobial drugs

chemotherapeutic agents used to treat microbial infections. Numerous different antimicrobial drugs are now available, each with characteristics that make it more or less suitable for a given clinical situation

Allylamines

inhibit an enzyme in the pathway of ergosterol synthesis. Naftifine and terbinafine can be applied to the skin to treat dermatophyt infections. Terbinafine can also be taken orally.

E test

modification of the disc diffusion test. Uses a strip containing a gradient o concentrations of an antimicrobial drug. Multiple strips containing different drugs are placed on the surface of an agar medium that has been inoculated with the test organism. During incubation the test organism will grow and a zone of inhibition will form around each strip.. Because of the gradient of drug concentrations the zone of inhibition will be shaped like a teardrop that intersects the strip at some point. MIC is determined by reading the printed number at the point where the bacterial growth intersects the strip