Antibiotic Drug Classes Flashcards

1
Q

At the most basic level, antimicrobial agents act through what four distinct major mechanisms of actions?

A

Inhibition of cell wall synthesis
Inhibition of protein synthesis
Inhibition of folic acid biosynthetic pathways Inhibition of DNA/RNA synthesis

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2
Q

Penicillins belong to a class of antibiotics known as ____

A

β-lactams (others include carbapenems and cephalosporins)

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3
Q

What are some examples of narrow-spectrum penicillins?

A

Oxacillin, Nafcillin

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4
Q

What are some examples of aminopenicillins?

A

Ampicillin, Amoxicillin

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5
Q

What are some examples of broad-spectrum penicillins?

A

Piperacillin.

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6
Q

What is the mechanism of action of penicillins?

A
  1. The first is the binding to penicillin-binding proteins.

2. The second is the destruction of the bacterial cell wall.

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7
Q

T or F. Virtually all bacteria contain penicillin-binding proteins

A

T. Different bacteria have different amounts and different types of penicillin-binding proteins. For example, Escherichia coli has seven types, and Staph. aureus has four.
Different penicillin-binding proteins have different affinities for β-lactams, and therefore different bacteria will demonstrate different sensitivities to β-lactams

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8
Q

How do B-lactams work?

A

by inhibiting transpeptidases, the enzymes that cross-link peptidoglycan molecules in bacterial cell walls. Cross-linking these molecules gives strength to the cell wall. Weak walls typically leads to lysis.

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9
Q

Are gram-positive or negative bacteria susceptible to B-lactams? Why?

A

Gram-positive bacteria have a thick peptidoglycan layer. They are therefore sensitive to β-lactams.

Gram-negative bacteria have a thinner peptidoglycan layer, but external to this layer is a lipopolysaccharide layer. This lipopolysaccharide layer protects the peptidoglycan layer from β-lactam activity, and therefore gram-negative bacteria are significantly more resistant to β-lactams.

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10
Q

What are β-Lactamase inhibitors?

A

these are added to some β-lactam antibiotics to overcome resistance caused by β-lactamase. Although β-lactamase inhibitors do contain a β-lactam, they are not toxic to the bacteria; they merely bind to β-lactamase.

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11
Q

What are some examples of β-lactamase inhibitors?

A

Clavulanic acid (added to amoxicillin) Tazobactam (added to piperacillin)

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12
Q

What are the positives and negatives of narrow-spectrum B-lactams?

A

Narrow-spectrum penicillins contain a larger molecule on the penicillin molecule side chain that confers steric hindrance: the inability to twist the molecule into other stereoisomers. This results in these penicillins being resistant to β-lactamase but at the same time restricts their spectrum of activity (thus they are said to be narrow-spectrum agents).

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13
Q

What are aminopenicillins used for?

A

Aminopenicillins have an added amino group (NH2) that makes the molecule more hydrophilic and thus able to cross the lipopolysaccharide layer more easily. Therefore aminopenicillins have greater activity against gram-negative bacteria.

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14
Q

What are the uses of broad-spectrum penicillins?

A

Broad-spectrum penicillins are modifications of aminopenicillins: nitrogen and carbon atoms are added to the molecule. This increases the range of bacteria that are sensitive to the antibiotic. These penicillins are usually co- administered with a β-lactamase inhibitor because they are β-lactamase sensitive (a common example is “Pip/Tazo,” which is piperacillin and tazobactam).

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15
Q

How does the drug aztreonam differ from penicillins and cephalosporins in its structure and function?

A

Unlike the penicillins and cephalosporins, which contain a thiazolidine ring attached to the β-lactam ring, aztreonam is a monobactam. The β-lactam ring contains a sulfonic acid group that gives aztreonam its activity. Like the penicillins and cephalosporins, aztreonam is mainly bactericidal and inhibits bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall.

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16
Q

How do Carbapenems (brand: Imipenem) differ structurally from penicillins?

A

The 5-membered ring at its core contains a carbon atom, rather than a sulfur atom.

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17
Q

What are the uses of Imipenem?

A

a) more efficient penetration through the bacterial cell wall,
b) resistance to bacterial enzymes. Imipenem has a high degree of stability in the presence of beta-lactamases, and is itself a potent inhibitor of beta-lactamases from certain gram-negative bacteria that may be inherently resistant to many beta-lactam antibiotics
c) affinity for all bacterial PBPs. Imipenem has a broader spectrum of activity than do many other beta-lactam antibiotics.

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18
Q

Imipenem is often given in combination with Cilastatin. Why?

A

Cilastatin is a reversible, competitive inhibitor of dehydropeptidase-1 (DHP-1), an enzyme found in the brush border of the proximal tubular cells of the kidneys that breaks down imipenem to inactive metabolites. By inhibiting this enzyme, cilastatin prevents the renal metabolism of imipenem, which results in an increase in urinary concentrations of imipenem from 15—20% to 60—70% and minimizes the nephrotoxicity observed when imipenem is administered alone. Cilastatin has no antimicrobial activity, nor does it interfere with imipenem’s actions

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19
Q

T or F. IN GENERAL, gram-positive activity
is lost with each successive drug generation of cephalosporins, whereas activity against gram-negative organisms is gained.

A

T

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20
Q

What are first generation cephalosporins use for?

A

useful in treating skin infections (which are commonly Streptococcus or Staphylococcus)

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21
Q

What are some common first generation cephalosporins and their uses?

A

Cefazolin is used commonly for surgical prophylaxis.

Cephalexin (1st gen; oral drug) is the most commonly prescribed cephalosporin for outpatient use.

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22
Q

What are second generation cephalosporins used for?

A

good for mild gram-negative Bacteroides infection (anaerobic), which can occur with intraabdominal infections.

They are used less commonly for severe infections because third-generation cephalosporins are more efficacious.

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23
Q

What is Ceftriaxone (3rd gen; IV; cephalosporin) commonly used for?

A

used commonly in the treatment of sexually transmitted diseases; it is also the drug of choice for treating pediatric meningitis

24
Q

What is Cefepime (3rd gen; IV; cephalosporin) commonly used for?

A

used to treat pseudomonal infections.

25
Q

What are fourth generation cephalosporins used for?

A

4th-generation cephalosporins are reserved for severe nosocomial (hospital-acquired) infections, which have a tendency to be resistant to multiple other antibiotics, more severe or commonly caused by gram-negative organisms.

26
Q

How does vancomycin work?

A

Glycopeptides like vancomycin inhibit cell wall synthesis by attaching to the end of the peptidoglycan precursor units (a short four- or five-amino acid sequence called the d-alanyl-d- alanine [D-ALA-D-ALA] terminus) that are required to be laid down into the matrix.

Glycopeptides are bactericidal in organisms that are dividing,
because a dividing bacterium requires new cell wall synthesis, and the absence of the new cell wall results in death of the organism.

27
Q

Are glycopeptide drugs like vancomycin effective against both gram positive and negative bacteria?

A

As a result of targeting the peptidoglycan layer, glycopeptides are effective only against gram-positive organisms. This is because gram-negative bacteria possess a thick outer layer of lipopolysaccharide that covers the peptidoglycan layer.

28
Q

How should glycopeptides like vancomycin be administered?

A

Glycopeptides like vancomycin are very poorly
absorbed from the GI tract. If the infection that is being treated is inside the GI tract then administering the drug orally provides the highest exposure of antibiotic to the infection. If the infection is anywhere other than inside the GI tract (e.g., blood, soft tissues, brain, heart), then the drug must be administered IV.

29
Q

How does Fosfomycin work?

A

Fosfomycin inhibits one of the first steps in the synthesis of peptidoglycan. After transport
into bacterial cells via glycerol-3-phosphate or glucose-6-phosphate transport systems,
fosfomycin, through its epoxide group, irreversibly inactivates the enzyme enolpyruvyl transferase by taking the place of phosphoenolpyruvate. Inactivation of this enzyme blocks the condensation of uridine diphosphate-N-acetylglucosamine with p-enolpyruvate, a key first step in bacterial cell wall synthesis. Fosfomycin also binds other p-enolpyruvate dependent enzymes, but irreversible inactivation does not occur. Inhibition of peptidoglycan synthesis results in accumulation of the nucleotide precursors and subsequent death and bacterial cell lysis.

30
Q

How do aminoglycosides fight bacteria?

A

they target and inhabit protein synthesis in various ways

31
Q

How are ahminoglycosides typically administered? Why?

A

These drugs have a polar structure and in consequence, penetration of biologic membranes is poor. Therefore all aminoglycosides are poorly absorbed in the GI tract and are not administered orally, and intracellular concentrations are usually low.

The exception to this rule is the proximal tubule in the kidney. Aminoglycosides accumulate inside these kidney cells, and this is the basis for nephrotoxicity of this drug.

32
Q

T or F. Eukaryotic and prokaryotic ribosomes have the same composition

A

F. Prokaryotes (bacteria) have 70S ribosomes made of a small (30S) and a large (50S) subunit. The 50S subunit is composed of a 5S and a 23S subunit plus 34 other proteins.

Eukaryotes (humans) have 80S ribosomes, composed of a small (40S) and a large (60S) subunit.

33
Q

What are the binding sites of ribosomes during translation?

A
  1. Aminoacyl (A): Incoming tRNA binds to this site.
  2. Peptidyl (P): This is where the existing amino acid chain (connected to tRNA) is
    elongated when the incoming amino acid is transferred to it through the action of peptidyl
    transferase.
  3. Exit or egress (E): After the tRNA gives up the amino acid chain, it must leave so that
    new tRNA can take its place.
34
Q

How do aminoglycosides work?

A

Two methods:
1) Aminoglycosides irreversibly bind the 30S ribosomal subunit (RSU). At low concentrations they cause misreading of the mRNA by ribosomes, leading to synthesis of proteins with incorrect amino acid sequences. At higher concentrations they halt protein synthesis, trapping the ribosomes at the AUG start codon. Accumulation of these abnormal initiation complexes halts translation.

2) Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures and pores in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake.
This rapid action at the outer membrane probably accounts for most of the bactericidal activity. Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake; therefore aminoglycosides are less active against anaerobes.

35
Q

What types of bacteria are aminoglycosides particularly effective against?

A

gram-negative bacteria.

NOTE: Many other protein synthesis inhibitors are bacteriostatic (only inhibit replication of bacteria versus killing bacteria). The action of aminoglycosides on the outer bacterial membrane, in addition to its protein synthesis inhibition, is thought to be the reason that aminoglycosides are bactericidal.

36
Q

Examples of brand aminoglycosides.

A
GENTAMICIN 
Amikacin 
Neomycin 
Streptomycin 
Tobramycin
37
Q

How are macrolides named?

A

Nomenclature of macrolides is similar to that of aminoglycosides (gentamicin) except that for macrolides, thro precedes the mycin.

38
Q

Examples of brand macrolides.

A

AZITHROMYCIN
CLARITHROMYCIN
ERYTHROMYCIN
Telithromycin (Ketolide)

39
Q

What are the structural differences between erythromycin and clarithromycin and azithromycin and their impact?

A

Erythromycin is unstable in gastric acid and therefore must be administered with salts or esters or via enteric-coated tablets when administered orally. The addition of a methyl group to erythromycin creates clarithromycin, and the addition of a methylated nitrogen to erythromycin creates azithromycin; both are stable in gastric acid and very well absorbed orally.

40
Q

How do macrolides work?

A

Macrolides like AZITHROMYCIN bind the 23S rRNA molecule of the 50S RSU and inhibit peptidyl transferase, blocking the transfer of the new amino acid onto the growing chain. Inhibition of protein synthesis does not typically kill bacteria cells, so these agents are generally bacteriostatic, but in high concentrations they can be bactericidal.

NOTE: Macrolides are phagocytosed by macrophages, which is a benefit because WBCs preferentially travel to sites of infection, thereby theoretically delivering the drug to the site at which it is needed. This is very convenient.

41
Q

How do lincosamides like Clindamycin work?

A

Lincosamides like CLINDAMYCIN bind the 23S rRNA molecule of the 50S RSU and inhibit peptidyl transferase, blocking the transfer of the new amino acid onto the growing chain. Inhibition of protein synthesis does not typically kill bacteria cells, so these agents are generally bacteriostatic but in high concentrations can be bactericidal. Clindamycin, because of its action on protein synthesis, has been postulated to be beneficial in toxin-producing infections; most bacterially produced toxins are proteins, so an added benefit of a protein synthesis inhibitor is reduced toxin production, in addition to slowed bacterial growth.

42
Q

How do tetrocyclines work?

Name brands:
DOXYCYCLINE 
TIGECYCLINE 
Minocycline
T etracycline
A

Tetracyclines must first enter the microorganism before they can exert their antimicrobial effects. Microbes that actively take in tetracycline develop increased susceptibility to the drug because intracellular levels of the drug are high.

Tetracyclines bind reversibly to the 16S subunit of the 30S RSU and inhibit translation (protein synthesis). Binding of tetracycline to the ribosome weakens the ribosome-tRNA interaction; this prevents addition of amino acids to the growing peptide. This is in contrast to antibiotics that bind the 23S subunit and inhibit the initiation of translation.
Because tetracyclines stop protein synthesis, they are bacteriostatic. When drug levels fall, the protein synthesis can continue.

Mammalian cells lack the active transport system that bacteria use to take up tetracycline; this provides part of the basis of selectivity of tetracyclines on microbes and not the host. Different ribosome shapes and sizes also confer selectivity of bacterial versus human ribosome binding.

43
Q

Common names of STREPTOGRAMINS.

A

Quinupristin and dalfopristin

44
Q

How does Quinupristin work?

A

It is a protein synthesis inhibitor that binds the 50S ribosomal subunit. Quinupristin binds at the same site as macrolides and has a similar effect, with inhibition of polypeptide elongation and early termination of protein synthesis.

45
Q

How does Dalfopristin work?

A

Dalfopristin binds at a site nearby, resulting in a conformational change in the 50S ribosome, synergistically enhancing the binding of quinupristin at its target site. Dalfopristin directly interferes with polypeptide-chain formation. In many bacterial species, the net result of the cooperative and synergistic binding of these two molecules to the ribosome is bactericidal activity.

46
Q

How does Mupirocin work?

A

It inhibits bacterial protein synthesis by reversible binding and inhibition of isoleucyl transfer-RNA synthetase. There is no cross-resistance with other classes of antibiotics.

47
Q

What types of bacteria are Mupirocin effective against?

A

The drug is applied topically and is bactericidal against many gram-positive and selected gram- negative bacteria

48
Q

How does Chloramphenicol work?

A

Chloramphenicol binds to the 50S ribosomal subunit at the peptidyltransferase site and inhibits the transpeptidation reaction. Chloramphenicol binds to the 50S ribosomal subunit near the site of action of clindamycin and the macrolide antibiotics. These agents interfere with the binding of chloramphenicol and thus may interfere with each other’s actions if given concurrently.






49
Q

How do FLUOROQUINOLONES work?

brand names:
CIPROFLOXACIN
Levofloxacin

A

DNA is normally supercoiled. Supercoiled DNA is under too much tension to be separated, so an extra step is required before replication and transcription can occur. DNA gyrase relaxes supercoiled DNA by cutting it, allowing rotation to occur, and then re- attaching it.

Fluoroquinolones bind to and inhibit DNA gyrase (also called topoisomerase II) and topoisomerase IV. The fluoroquinolones inhibit DNA gyrase after the cutting step, preventing reattachment from occurring. At high doses this leads to the release of these broken segments of DNA. It is thought that the accumulation of these DNA fragments leads to cell death, accounting for the bactericidal action of fluoroquinolones.

Fluoroquinolones inhibit DNA gyrase in gram- negative organisms and topoisomerase IV in gram- positive organisms.

NOTE: Eukaryotes (humans) possess different forms of topoisomerase II and topoisomerase IV.

50
Q

How do RIFAMYCINS work?

brand names:
RIFAMPIN
Rifaximin

A

RNA polymerase reads DNA to produce an mRNA copy of the genetic code. Without RNA, protein synthesis cannot occur.

Rifampin inhibits bacterial RNA synthesis by binding prokaryotic (bacterial) RNA polymerase. It prevents initiation of RNA synthesis (but not elongation of RNA).

Rifampin does not bind human RNA polymerase, so its action on RNA synthesis is limited to bacterial RNA, which serves to limit its side effects.

51
Q

How does the lipophilic nature of Rifamycins make them so effective?

A

Rifampin is highly lipophilic. This is extremely important because it confers the property that the drug can easily cross lipophilic membranes:

  1. Mycobacterial cell walls contain mycolic acids, which are long fatty acids and therefore lipids. Rifampin therefore easily and readily enters mycobacterial cells.
  2. Biofilms (inert films that bacteria can live in) created by some bacteria (e.g., S. epidermidis and S. aureus) generate a barrier that antibiotics generally cannot enter. However, rifampin can enter the biofilms because of its lipophilic nature.
  3. CNS distribution is high (and therefore rifampin is effective for CNS infections such as bacterial meningitis).
  4. Rifampin enters phagocytic cells and therefore can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and organisms inside abscesses, which do not have good blood supplies.
52
Q

How does Metronidazole work? What kinds of bacteria is it useful against?

A

Metronidazole is a prodrug. The nitrogen group must be reduced (addition of electron) before the chemical obtains its anti-infective function. It is reduced by a nitroreductase enzyme called a ferredoxin (an iron- and sulfur-containing enzyme). The extra nitrogen side chain is reduced in this reaction.

With aerobic bacteria the electron transport chain does not require these special enzymes because oxygen is the terminal electron acceptor; therefore the prodrug is not converted to the active form of the drug. However, with anaerobic bacteria, with which oxygen is absent, these special enzymes are present. Therefore metronidazole is not activated with aerobic bacteria but is particularly effective against anaerobic bacteria.

Reduction of the prodrug metronidazole results in the production of toxic products (hydroxylamine) and other free radicals that damage DNA.

53
Q

How does COTRIMOXAZOLE work? What is a combination of?

A

it is a DHFR Inhibitor. Cotrimoxazole is a combination drug comprised of trimethoprim and sulfamethoxazole

The antimicrobial activity of the combination product results from its actions on two steps of the enzymatic pathway for the synthesis of tetrahydrofolic acid. Sulfonamide inhibits the incorporation of PABA into folic acid, and trimethoprim prevents the reduction of dihydrofolate to tetrahydrofolate.

The synergistic interaction between sulfonamide and trimethoprim is predictable from their respective mechanisms. There is an optimal ratio of the concentrations of the two
agents for synergism that equals the ratio of the minimal inhibitory concentrations of the drugs acting independently. Although this ratio varies for different bacteria, the most effective ratio for the greatest number of microorganisms is 20 parts sulfamethoxazole to 1 part trimethoprim

54
Q

Why are DHFR inhibitors such as cotrimoxazole effective against microorganisms and not toxic to humans?

A

Selective toxicity for microorganisms is achieved in two ways. Mammalian cells use preformed folates from the diet and do not synthesize the compound. Furthermore, trimethoprim is a highly selective inhibitor of dihydrofolate reductase of lower organisms: ~100,000 times more drug is required to inhibit human reductase than the bacterial enzyme. This relative selectivity is vital because this enzymatic function is essential to all species.

55
Q

What is cotrimoxazole used for?

A

Useful for uncomplicated UTI, and for acute exacerbations of chronic bronchitis. Also effective against infection by Pneumocystis jiroveci.

56
Q

How does DAPTOMYCIN work?

A

Lipopeptide antibiotics like daptomycin interfere with the integrity of cell wall structure in gram-positive bacteria via a unique mechanism of action. Specifically, lipopeptides bind to
bacterial membranes and cause a rapid depolarization of membrane potential; they do not penetrate the bacterial cytoplasm. This loss of membrane potential leads to inhibition
of protein, DNA, and RNA synthesis and, eventually, bacterial cell death. Lipopeptides appear to be bactericidal against gram-positive bacteria. Ironically, the unique mechanism causes it to be inactivated by pulmonary surfactant. Pulmonary surfactant is primarily dipalmitoylphosphatidylcholine with significant amounts of phosphatidylglycerol, which is also a prominent component of gram-positive bacterial membranes. These phospholipids interact with daptomycin and sequester the antibiotic, thereby preventing it from exerting its antibacterial effects. Phase 3 clinical trials in community-acquired pneumonia showed reduced efficacy of daptomycin.

57
Q

How does FIDAXOMICIN work?

A

A highly specialized drug indicated only for the treatment of pseudomembranous colitis or C. Diff associated diarrhea. Fidaxomicin inhibits RNA synthesis by inhibiting sigma-dependent transcription of bacterial RNA polymerases and may act at the early stages of transcription. There is no cross-resistance with other classes of antibacterial agents, including the rifamycin class as the site of action for fidaxomicin is thought to be distinct from that of the rifamycins, which also act on RNA polymerases.