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Pharmacology > Antibacterial drugs > Flashcards

Antibacterial drugs Flashcards

1
Q

Define

Post-antibiotic effect (PAE)

A

The persistent suppression of microbial growth that occurs even after levels of antibiotic have fallen below the MIC

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2
Q

Define

Minimum inhibitory concentration (MIC)

A

The lowest concentration of an antibiotic that prevents visible microbial growth

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3
Q

Define

Minimum bactericidal concentration (MBC)

A

The lowest concentration of an antibiotic that reduces the number of viable cells by at least 1000-fold

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4
Q

What is the factor by which a bactericidal antibiotic at its MBC reduces the number of viable cells?

A

1000-fold

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5
Q

Define

Attainable antibiotic level (AAL)

A

The concentration of an antibiotic that can be reached in target tissues without causing toxic or side effects

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6
Q

How does the MBC of a truly bactericidal drug compare to its MIC?

A

The MBC is equal to or slightly greater than the MIC

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7
Q

What are examples of antibacterials that have a long PAE?

A
  • Aminoglycosides
  • Fluoroquinolones
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8
Q

Fluoroquinolones are antibacterials with long PAEs. How does this affect their dosage?

A

They require only one dose per day

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9
Q

For some antibacterial drugs, the trough level is lower than the MIC. However, these drugs are still therapeutically useful. How is this?

A
  • The drugs have a notable post-antibiotic effect (PAE)
  • There is synergism between host defenses and sub-MIC levels of the antibiotic
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10
Q

What is a negative implication of an antibacterial having low trough levels?

A

Development of drug-resistant strains of bacteria

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11
Q

At which trough concentrations of antibacterial is the likelihood of developing antibiotic resistance greatly increased?

A
  • Levels below the MIC
  • Levels at the MIC
  • Levels slightly above the MIC

(depending on the drug)

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12
Q

Where are common sites of action of antibacterials in bacterial cells?

A
  • Cell wall
  • Plasma membrane
  • DNA
  • RNA
  • Ribosomes (protein synthesis)
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13
Q

How do antibacterials targeting the cell wall function?

A

Inhibiting the formation of peptidoglycans that are essential in cell wall formation. This disruption of the cell wall causes death of the bacterium

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14
Q

How do antimicrobials targeting the plasma membrane function?

A

Interfering with the permeability or function of the plasma membrane

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15
Q

How do antibacterials targeting the DNA function?

A

Inhibiting DNA synthesis and replication

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16
Q

How do antibacterials targeting RNA function?

A

Inhibiting RNA synthesis

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17
Q

How do antibacterials targeting protein synthesis function?

A

Inhibiting the 30S and/or 50S subunits of ribosomes

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18
Q

What are examples of antibacterials that interfere with bacterial metabolism?

A
  • Sulfonamides
  • Trimethoprim
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19
Q

What is the pathway that sulfonamides and trimethoprim act on?

A

para-aminobenzoic acid → dihydrofolate (DHFA) → tetrahydrofolate (THFA)

  • Sulfonamides inhibit the synthase forming DHFA
  • Trimethoprim inhibits the reductase forming THFA
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20
Q

How are antimicrobials classified?

A
  • Mechanism of action
  • Chemical structure
  • Spectrum of antimicrobial activity
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21
Q

What are the types of narrow-spectrum drugs?

A
  • Those effective in Gram-positive cocci and bacilli
  • Those effective in Gram-negative bacilli (e.g. aminoglycosides)
  • Those only effective in specific infections (e.g. isoniazid is only effective against Mycobacterium tuberculosis)
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22
Q

What is an example of a drug with narrow-spectrum action against Gram-negative bacilli?

A

Aminoglycosides

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23
Q

What is an example of a drug effective only against TB?

A

Isoniazid

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24
Q

What are broad-spectrum drugs?

A

Those effective against Gram-positive and Gram-negative cocci and bacilli

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25
Q

What is a negative implication of using broad-spectrum antibacterials?

A

These drugs can alter the nature of the normal flora and precipitate a superinfection

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26
Q

What are extended-spectrum drugs?

A

Agents that are effective against Gram-positive organisms and against a significant number of Gram-negative bacteria, or against a specific microorganism

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27
Q

What is an example of an extended-spectrum antibiotic?

A

Antipseudomonal penicillins

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28
Q

What is the major consideration in the use of antibacterial drugs?

A

The identification of the causative microorganism and the use of the proper drug for an adequate duration

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29
Q

What are the factors affecting the choice of antimicrobial agent?

A
  • The causative microorganism and its susceptibility
  • Pharmacokinetic factors
  • Toxicity and side effects
  • Interactions with other drugs
  • Cost
  • Host factors
  • Genetic factors
  • Pregnancy
  • Lactation
  • Local factors at the site of infection
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30
Q

How can the causative organism of an infection be determined?

A
  • Clinical picture
  • Culture and sensitivity
  • Serology
  • PCR
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31
Q

What are some of the pharmacokinetic factors affecting choice of antimicrobial agent?

A
  • The site of infection (e.g. if in the CNS, the drug must cross the blood–brain barrier)
  • The presence of renal disease that affects clearance
  • The presence of liver disease that affects metabolism and elimination
  • The route of administration
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32
Q

What are examples of host factors?

A
  • Age
  • Allergic reaction to a given antimicrobial agent
  • Host defense mechanisms (e.g. immunodeficiency or immune suppression)
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33
Q

What is an example of genetic factors affecting selection of an antimicrobial drug?

A

Those with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at risk of severe hemolysis if they take sulfonamides, chloramphenicol, or nitrofurantoin

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34
Q

What are the concerns of using antimicrobial drugs in pregnancy?

A

They may be teratogenic

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35
Q

What is an example of a local factor at the site of infection that affects chemotherapy?

A

The presence of an abscess means use of chemotherapeutic drugs will not be effective

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36
Q

Under which conditions does bacterial resistance occur?

A
  • The clinical condition of the host is impaired
  • The normal flora has been suppressed
  • Interrupted or inadequate chemotherapy
  • Widespread use of broad spectrum antibiotics
  • Poor environmental setting of the host
  • More frequent in certain types of bacteria (e.g. Gram-negative bacteria)
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37
Q

What are the mechanisms of bacterial resistance?

A
  • Natural resistance
  • Acquired resistance
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38
Q

What are the types of natural bacterial resistance?

A
  • Absence of a metabolic process, enzyme, or protein in the bacterium that is required for the action of the antimicrobial
  • Absence or tough cell wall, making it difficult for the antimicrobial to penetrate and enter the cell
  • Low concentration (subtherapeutic) of the antimicrobial drug at the site of action, compared to its plasma concentration (overcome by highering the dose, which also leads to adverse effects)
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39
Q

What are the types of acquired bacterial resistance?

A
  • Mutation or genetic change
  • Adaptation, e.g. production of β-lactamases
  • Infectious or multiple drug resistance, acquired through
    • transduction via a phage,
    • transformation using exogenous DNA, or
    • conjugation with another bacterium
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40
Q

Define

Acquired bacterial resistance

A

Development of resistance in a previously sensitive microorganism population

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41
Q

What is the most common reason for acquired bacterial resistance?

A

Misuse or abuse of antibiotics, e.g.

  • Improper dose and duration of action
  • Prescribing antibiotics for suppurative diseases (with abscesses)
  • Prescribing antibacterials for viral infections
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42
Q

What are some specific examples of antibacterial resistance?

(how the cell is resistant, not how it acquires the resistance)

A
  • Generating enzymes that inactivate the antibiotic (e.g. β-lactamase)
  • Changing the structure of a target effector (e.g. penicillin-binding protein for β-lactam drugs and aminoglycosides)
  • Membrane proteins or efflux pumps that prevent cellular accumulation of the antibiotic (prominent in Gram-negative bacteria, usually an issue for tetracyclins)
  • Changing the metabolic pathway that is being blocked (e.g. the DHFA synthase blocked by sulfonamides)
  • Overproducing the target enzyme/protein to overpower the effect of the drug
  • Mycoplasmas lack a cell wall, making them resistant to penicillins
  • Circumventing the targeted metabolic process (e.g. sulfonamides don’t affect bacteria that obtain reduced folate from the environment)
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43
Q

What are the indications of combined antibacterial therapy?

A
  • Obtaining synergism, or being able to reduce the dose of a toxic drug
  • Reducing the emergence of resistance
  • Treating mixed infections with microorganisms of different sensitivities
  • Treating infections at different, privileged anatomical sites (e.g. bile, cerebrospinal fluid)
  • Treating infections of unknown etiology, especially in patients at high risk of developing infection (e.g. AIDS patients)
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44
Q

What are the outcomes of combined chemotherapy?

A
  • Indifference (the most common outcome)
  • Antagonism (e.g. when using a cidal and a static, the static inhibits division of cells, so the cidal’s function is impaired)
  • Synergism (e.g. with penicillins and aminoglycosides, the penicillin increases permeability of the cell wall allowing for aminoglycoside entry, and the aminoglycoside inhibits protein synthesis, thus decreasing synthesis of cell wall)
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45
Q

What are the disadvantages of combined chemotherapy?

A
  • Increased toxicity
  • Increased cost
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46
Q

What are the indications of prophylactic antibacterial therapy?

A
  • Protection of healthy individuals at risk of highly contagious diseases or infections (e.g. syphilis, gonorrhea, TB, meningococcal meningitis)
  • Preventing secondary or opportunistic infections in very ill patients (e.g. AIDS patients, before major surgeries, before labor and delivery, organ transplantations, recurrent UTIs)
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47
Q

When is prophylactic use of antibacterials successful?

A
  • A single antibacterial drug is used
  • The dose needed for prophylaxis is lower than the therapeutic dose
  • The drug is needed for a brief period (chronic therapy can lead to resistance)
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48
Q

What are complications of antibacterial therapy?

A
  • Hypersensitivity (allergy or otherwise; the most frequent and serious adverse effect)
  • Direct toxicity (to the liver, kidney, or other)
  • Superinfections, precipitated by alterations to the normal flora, allowing for overgrowth of normally opportunistic pathogens, especially fungi and resistant bacteria (e.g. C. difficile)
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49
Q

What are the classes included in the β-lactam drugs?

A
  • Penicillins
  • Cephalosporins
  • Carbapenems
  • Carbacephems
  • Monobactams
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50
Q

What is the unifying characteristic of the β-lactam drugs?

A

An intact β-lactam ring (a four-membered ring containing [at least] a nitrogen atom in the ring and an oxygen doubly bonded to the ring)

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51
Q

The β-lactam drugs have, as part of their general structure, a highly substituted R group linked by an amide to the β-lactam ring. What is the significance of this R group?

A

The precise structure of the R group determines the characteristics of the the specific antimicrobial drug, e.g.

  • Narrow or broad spectrum
  • Route of administration
  • Sensitivity of target organisms
  • Resistance to β-lactamases
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52
Q

What are the agents that degrade the β-lactam ring?

A
  • Gastric acid
  • β-lactamases
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53
Q

What is the general mechanism of action of the β-lactam drugs?

A
  • Inhibit synthesis of bacterial cell wall by binding to proteins in the cell membrane, e.g. penicillin-binding proteins
  • Binding produces a defective cell wall that allows the intracellular contents to leak out (lysis)
  • Most effective when bacterial cells are dividing (as they produce new cell wall during this time)
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54
Q

What are examples of species that produce β-lactamase?

A
  • Staphylococcus aureus
  • Moraxella catarrhlis
  • Neisseria gonorrhoeae
  • Enterobacteriaceae spp.
  • Hemophilus influenzae
  • Bacteroides spp.
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55
Q

What are the general characteristics of penicillins (PCNs)?

A
  • Most widely used antibiotics
  • Most effective
  • Least toxic
  • Cheap
  • Derivatives of 6-aminopenicillanic acid
  • Derived from a fungus
  • The prototype drug is penicillin G
  • Widely distributed in the body, except in the CSF (unless inflammation is present) and the intraocular fluid
  • Complications include hypersensitivity, seizures, and nephropathy
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56
Q

What are the natural penicillins?

A
  • Penicillin G (benzylpenicillin)
  • Penicillin V (phenoxymethylpenicillin)

None of the other natural penicillins are currently used therapeutically

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57
Q

How is benzylpenicillin (penicillin G) administered?

A
  • Acid labile and short acting, so it is not effective orally
  • Penicillin G procaine is given IM twice daily
    • Seriously contraindicated IV as it leads to lowered blood pressure and convulsions
  • Penicillin G benzathine is given IM once monthly for rheumatic fever prophylaxis
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58
Q

How is phenoxymethylpenicillin (penicillin V) administered?

A

Orally

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59
Q

What are the therapeutic characteristics of the natural penicillins?

A
  • Narrow spectrum
  • Sensitive to penicillinase (a type of β-lactamase)
  • Drugs of choice to treat infections with β-hemolytic type A streptococci
  • Little effect, if any, against Gram-negative bacteria

(penicillins G and V)

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60
Q

What are the narrow-spectrum, penicillinase-resistant (anti-Staph) penicillins?

A
  • Nafcillin
  • Oxacillin
  • Cloxacillin
  • Dicloxacillin
  • Flucloxacillin
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61
Q

What are the broad-spectrum, penicillinase-sensitive (aminopenicillin) penicillins?

A
  • Ampicillin
  • Amoxicillin: given orally; more potent, better bioavailability, and longer DOA than ampicillin
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62
Q

What are the therapeutic characteristics of the aminopenicillins?

A
  • Have little effect, if any against:
    • penicillinase-producing bacteria, e.g. Hemophilus influenzae
    • Gram-negative bacteria, e.g. E. coli, Proteus spp.
  • No effect against pseudomonas
  • Widely used in tonsillitis, otitis media, gonorrhea, respiratory infections, shigella infections, and UTIs
  • Amoxicillin has good activity against H. pylori in peptic ulcers (with PPIs, with or without clarithromycin and metronidazole)

(ampicillin, amoxicillin)

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63
Q

What are the diseases treated using aminopenicillins?

A
  • Otitis media
  • Tonsilitis
  • Gonorrhea
  • Respiratory infections
  • Shigella infections
  • UTIs
  • H. pylori-related peptic ulcers

(ampicillin, amoxicillin)

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64
Q

What are the antipseudomonal penicillins?

A
  • Piperacillin >
  • Mezlocillin =
  • Ticarcillin >
  • Carbenicillin

(relative potencies given)

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65
Q

What are the amidinopenicillins?

A
  • Mecillinam
  • Pivmecillinam
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66
Q

What are the therapeutic characteristics of the amidinopenicillins?

A
  • Most potent PCNs against enterobacteria (Salmonella , Shigella, Klebsiella, E. coli, etc)
  • Little or no activity against Gram-positive cocci and pseudomonas
  • Synergistic with other β-lactams but not with aminoglycosides

(mecillinam, pivmecillinam)

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67
Q

What are the most potent penicillins against enterobacteria?

A

The amidinopenicillins (mecillinam, pivmecillinam)

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68
Q

What are the penicillins suitable for use against pseudomonas?

A
  • Piperacillin
  • Mezlocillin
  • Ticarcillin
  • Cabernicillin
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69
Q

What is the mechanism of action of penicillins?

A
  • Inhibit transpeptidases, the enzymes that catalyze the final cross-linking step in the synthesis of peptidoglycan
  • Disruption of the cell wall causes death of the bacterial cell, thus all PCNs are bactericidal
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70
Q

Are the penicillins bactericidal or bacteriostatic?

A

Bactericidal

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71
Q

What are the general pharmacokinetic properties of the penicillins?

A
  • Absorption: many have poor oral bioavailability, while others are suitable orally
  • Distribution:
    • bind plasma proteins, are widely distributed;
    • have low concentrations in the ocular fluid, joints, and CSF (do not cross the BBB unless the meninges are inflamed);
    • do not cross the placenta
  • Metabolism: by the liver
  • Excretion: usually in the kidney by glomerular filtration and tubular secretion
    • probenecid (a drug used for gout and hyperuricemia) inhibits tubular secretion of PCNs, increasing their half-life
    • naficillin and oxacillin are mainly excreted by the liver
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72
Q

What are the indications for the penicillins?

A
  • More effective in treating Gram-positive infections (the outer membrane of the Gram-negative organisms decreases efficacy)
  • Used to treat infections of the skin, genitourinary system, GI tract, respiratory tract, and soft tissues
  • Selection of the specific PCN depends on the organism and severity of the infection
  • Combination of PCNs with a potent inhibitor of lactamases broadens the spectrum
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73
Q

What are the β-lactamase inhibitors?

A
  • Clavulanic acid
  • Sulbactam
  • Tazobactam
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74
Q

What is the action of the β-lactamase inhibitors?

A
  • Have no intrinsic antibacterial activity
  • Inhibit bacterial β-lactamases to potentiate and broaden the spectrum of β-lactam drugs
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75
Q

What are common combinations of penicillins with β-lactamase inhibitors?

A
  • Augmentin: amoxicillin/clavulanate
  • Unasyn: ampicillin/sulbactam
  • Zosyn: piperacillin/tazobactam

Note: using β-lactamase inhibitors means the dose of the PCN can be lowered

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76
Q

What are the mechansisms of resistance to PCNs specifically?

A
  • Altered penicillin-binding proteins
  • Production of β-lactamases (e.g. penicillinases)
  • Decreased penetration
  • In pseudomonas, increased efflux pumps
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77
Q

What are the available preparations of PCNs?

A
  • Oral
  • Parenteral (mostly IM and IV)
  • Intrathecal
  • Topical
  • Intra-articular
78
Q

What are the common side effects to PCNs?

A

Hypersensitivity (most frequent and dangerous)

  • Type I (immediate): early onset (IgE-mediated)
  • Type II: may manifest as eosinophilia, hemolytic anemia, interstitial anemia, serum sickness (fever, arthralgia, malaise)
  • Nonallergic ampicillin rash: usually only occurs once (more common in patients with mononucleosis, lymphomas, cytomegalovirus infection)

Other

  • Neurotoxicity (especially for oxacillin and IV benzylpenicillin)
  • Hepatotoxicity (espeically for IV oxacillin)
  • Reversible bone marrow depression (especially for IV naficillin)
  • Nephrotoxicity (especially for methicillin, which has been mostly withdrawn from the market)
79
Q

What are the contraindications of PCNs?

A
  • Hypertension or heart failure (only for preparations with sodium)
  • Renal failure (only for preparations with potassium)
  • Absolute contraindication to all PCNs in patients with history of β-lactam or penicillin allergy
80
Q

What are the general characteristics of cephalosporins?

A
  • Derivatives of 7-aminocephalosporanic acid
  • Semisynthetic
  • Broad spectrum
  • Inhibitors of cell wall synthesis
  • Differ in pharmacokinetic properties and spectrum of activity
  • Classified into 5 generations, mostly based on history of discovery and somewhat on spectrum of activity
81
Q

What are the first-generation cephalosporins?

A
  • Cefadorxil
  • Cefalexin: oral
  • Cefazolin: IM, IV
  • Cefapirin
  • Cefradine
  • Cefaloridine
82
Q

What are the second-generation cephalosporins?

A
  • Cefaclor: oral
  • Cefamandole: IM, IV
  • Cefmetazole
  • Cefonicid
  • Cefotetan
  • Cefoxitin
  • Cefprozil
  • Cefuroxime
  • Cefuroxime axetil (prodrug of cefuroxime)
  • Loracarbef (technically a carbacephem)
83
Q

What are the third-generation cephalosporins?

A
  • Cefixime: oral
  • Cefoperazone
  • Cefdinir
  • Cefotaxime
  • Ceftriaxone
  • Cefpoxodime
  • Ceftazidime
  • Ceftibuten
  • Ceftizoxime
84
Q

What are the fourth-generation cephalosporins?

A
  • Cefepime: IM, IV
85
Q

What are the fifth-generation cephalosporins?

A
  • Ceftaroline: IV
86
Q

How do the generations of the cephalopsorins compare by distribution of spectrum of activity?

A
  • First generation have the best activity against Gram-positives and are less resistant to β-lactamases
  • Second, third, and fourth generations cross the BBB more readily
87
Q

What are the therapeutic uses of cephalosporins?

A
  • Never the first line therapy for any infection
  • Highly effective in:
    • Upper and lower respiratory infections
    • Hemophilus influenzae
    • UTIs
    • Dental infections
    • Severe systemic infections
88
Q

Which cephalosporin has the best activity against Bacteroides fragilis

A

Cefoxitin (2nd gen)

89
Q

Which cephalosporin has the best activity against H. influenzae?

A

Cefamandole (2nd gen)

90
Q

Which cephalosporins have the best activity against Pseudomonas aeruginosa?

A
  • Cefoperazone (3rd gen)
  • Ceftazidine (3rd gen)
  • Cefepime (4th gen)
91
Q

Which cephalosporin has the broadest Gram-positive spectrum of activity?

A

Ceftaroline:

  • Active against MRSA
  • Has some activity against Gram-negatives
92
Q

What are the adverse effects to cephalosporins?

A
  • Allergy: 10% of patients with penicillin allergy have cross-reactivity with cephalosporins
  • Hepatotoxicity
  • Nephrotoxicity: especially with cephaloridine (1st gen), risk increases with concomitant aminoglycoside use
  • Disulfiram-like reaction (severe nausea and vomiting): cefamandole, cefoperazone, ceftriaxone, cefmetazole
  • Hemolytic anemia
93
Q

How are cephalosporins excreted?

A

All by the kidney except ceftriaxone (3rd gen), by the liver

94
Q

What are the carbapenems?

A
  • Imipenem
  • Meropenem
95
Q

What are the therapeutic characteristics of imipenem?

A
  • Broadest spectrum of activity of all β-lactam drugs: effective against most Gram-positive and Gram-negative bacteria and anaerobes
  • β-lactamase resistant
  • More potent against E. faecalis, B. fragilis and Pseudomonas aeruginosa than 3rd gen. cephalosporins
  • Considered by some the drug of choice in the management of polymicrobial pulmonary, intra-abdominal, and tissue infections
96
Q

What are the pharmacokinetic properites of imipenem?

A
  • Administration: IV or IM
  • Metabolism: in the kidney by the enzyme dehydropeptidase I, so it is combined with cilastatin (an inhibitor of the enzyme)
  • Excretion: kidney
97
Q

What are the adverse effects of imipenem?

98
Q

What are the properties of meropenem?

A
  • Similar activity to imipenem
  • Resistant to dehydropeptidase I, so cilastatin is not used concomitantly
  • Lower incidence of seizures
99
Q

What are the carbacephems?

A

Loracarbef (also considered a second generation cephalosporin)

100
Q

What are the properties of the carbacephems?

A
  • Similar to 2nd gen. cephalosporins (especially cefaclor and cefprozil)
  • Effective orally
  • Excreted by the kidney
101
Q

What are the monobactams?

102
Q

What are the properties of monobactams?

A
  • Excellent activity against Gram-negatives
  • Little to no effect on Gram-positives
  • β-lactamase resistant
  • Considered a substitute to aminoglycosides in treating Gram-negative infections (less toxic)
  • Rarely, cause allergic reactions in patients with type I hypersensitivity to other β-lactam drugs
103
Q

What are the glycopeptides?

A
  • Vancomycin
  • Teicoplanin
104
Q

What are the therapeutic properties of glycopeptides?

A
  • Narrow spectrum of activity
  • Effective against Gram-positive bacteria, especially against MRSA
  • Used as alternatives to penicillins
  • Considered the drug of choice to treat pseudomembranous colitis and antibiotic-associated diarrhea (from C. dificile or Staph. enterocolitis), with or without metronidazole
105
Q

What are the pharmacokinetic properties of glycopeptides?

A
  • Administration:
    • Vancomycin: given IV as oral absorption is poor; but can be given orally in pseudomembranous colitis
    • Teicoplanin: IM
106
Q

What are the adverse effects of glycopeptides?

A
  • Rapid IV administration: flushing, tachycardia, lowered blood pressure, erythroderma (red man syndrome)
  • Thrombophlebitis (inflammation of the wall of a vain associated with thrombosis)
  • Ototoxicity
  • Circumoral paresthesia (pins and needles)
107
Q

What is the mechanism of action of glycopeptides?

A
  • Prevent the cross-linking of peptidoglycans
  • Thus, bactericidal
108
Q

What are the aminoglycosides?

A
  • Streptomycin
  • Gentamicin
  • Netilmicin
  • Kanamycin
  • Tobramycin
  • Amikacin
  • Neomycin
  • Paromomycin
109
Q

What are the common properties of aminoglycosides?

A
  • They all contain amino sugars and a cyclohexane ring
  • They have a similar spectrum of activity: highly effective against Gram-negative bacteria (some are broader but are still most used for Gram-negatives)
  • Bactericidal
  • Ineffective orally
  • Interfere with the bacterial membrane and inhibit bacterial protein synthesis by binding the 30S subunit
  • Do not bind plasma or tissue proteins
  • Have a small AVD (25% of body weight) and do not penetrate the BBB or the eye
  • Rapidly excrete unchanged by the kidney (they are not secreted or resorbed)
  • Are highly toxic and have a narrow therapeutic window
110
Q

What are the general toxic effects of aminoglycosides?

A
  • Ototoxicity: hearing and balance issues due to toxicity to the cranial nerve VIII. Reversible but severe toxicity may lead to deafness
  • Nephrotoxicity: acute tubular necrosis
  • Curare-like effect (muscle paralysis due to neuromuscular blockade)
  • Allergy
111
Q

Which aminoglycoside is most toxic?

A

Neomycin—it is only used topically and orally (for local GI tract infections)

112
Q

Which aminoglycoside is the drug of choice for neonatal Gram-negative meningitis?

A

Gentamicin. It is administered intrathecally as it does not cross the BBB

113
Q

Which aminoglycoside is the drug of choice for brucellosis and TB?

A

Streptomycin

114
Q

In which groups is dose adjustment necessary when administering aminoglycosides?

A
  • Children and old patients
  • Patients with renal disease
  • Patients with hypotension
  • Patients on diuretics
115
Q

What are the clinical uses of gentamicin, netilmicin, tobramycin, and amikacin?

A
  • Very potent against Gram-negative bacilli (e.g. E. coli, Klebsiella, Proteus, Pseudomonas)
  • Synergistic effects with the antipseudomonal PCNs
  • Strains of bacteria resistant to gentamicin could be sensitive to amikacin and vice versa
116
Q

What are the clinical uses of netilmicin?

A

Similar to gentamicin but less ototoxic. Effective against infections resistance to gentamicin

117
Q

What are the clinical uses of kanamycin?

A

Similar to netilmicin but with no antipseudomonal activity

118
Q

What are the clinical uses of neomycin?

A
  • Used to sterilize the bowel before abdominal surgeries (alongside erythromycin) as prophylaxis
  • Also used locally on the skin and the eye
  • Highly nephrotoxic, so it is never administered systemically
119
Q

What are the clinical uses of streptomycin?

A
  • Highly effective against TB
  • Used alongside PCNs to treat endocarditis due to streptococci
  • Highly effective against brucellosis
  • Administered IM, which leads to generalized muscle weakness
120
Q

What are the clinical uses of paromomycin?

A
  • Effective only in treating tapeworm infestation and intestinal amebiasis
  • It is a first-line treatment for amebiasis or giardiasis during pregnancy
121
Q

Which aminoglycosides are particularly ototoxic?

A

Kanamycin > amikacin&raquo_space; gentamicin = tobramycin

122
Q

Which aminoglycosides are particularly nephrotoxic?

A

Neomycin&raquo_space;> gentamicin = amikacin > tobramycin

123
Q

What are the macrolide antibiotics?

A
  • Erythromycin
  • Clarithromycin
  • Azithromycin
  • Oleandomycin
  • Telithromycin
  • Roxithromycin
  • Spiramycin
124
Q

What are the general properties of macrolides?

A
  • Bacteriostatic
  • Contain a lactone ring and sugars (a 12–22 carbon lactone ring linked to sugars)
  • Inhibits with the translocation process of protein synthesis
  • Given orally
  • Distribute well but cross well-inflamed meninges
125
Q

What is the mechanism of action of aminoglycosides?

A
  • Interfere with the bacterial membrane
  • Inhibit bacterial protein synthesis by binding the 30S subunit
126
Q

What is the mechanism of action of macrolides?

A

Inhibit with the translocation process of protein synthesis

127
Q

What are the clinical uses of erythromycin?

A
  • High activity against Gram-positive bacteria
  • Little effect against Gram-negative bacteria
128
Q

What are the clinical uses of clarithromycin and azithromycin?

A
  • More effective than erythromycin against several Gram-negatives, as well as against Mycoplasma pneumoniae, Helicobacter pylori, Toxoplasma gondii, cryptosporidia, and sever atypical mycobacteria
  • Clarithromycin is a second-line drug to PCNs in treating streptococcal and staphylococcal infections, e.g. tonsillitis in patients with PCN allergy
129
Q

What are the clinical uses of macrolides?

A
  • Drugs of choice in treating Corynebacterium diphtheriae and Mycoplasma pneumoniae (alongside tetracyclines)
  • Considered alternatives to PCNs in treating streptococcal and staphylococcal infections, e.g. tonsillitis in patients with PCN allergy (especially clarithromycin)
  • Considered second-line therapy for treatment of dental infections
130
Q

Why are macrolides never given as first-line therapy in treating dental infections?

A
  • They are bacteriostatic
  • Resistance to them develops easily
  • Less effective than PCNs in orodental infections and more toxic
131
Q

What are the side effects to macrolides?

A
  • GI irritation: major side effect and most frequent
  • Allergy
  • Cholestatic hepatitis: occurs due to direct toxicity or as a hypersensitivity reaction. Reversible, more common in adults, and more common with the estolate (gastric acid–resistant) form of erythromycin
132
Q

What is the mechanism of chloramphenicol?

A

Inhibits protein synthesis by inhibiting transpeptidation

133
Q

What are the properties of chloramphenicol?

A
  • Bacteriostatic
  • Broad spectrum: Gram-positive and Gram-negative bacteria as well as anaerobes
  • Highly lipid soluble—effective orally and widely used as local application on the eye
  • The best antibiotic in crossing the BBB
  • Metabolized to inactive metabolites by conjugation with glucuronide
134
Q

Which antibiotic crosses the BBB best?

A

Chloramphenicol

135
Q

What are the clinical uses of chloramphenicol?

A
  • Treating H. influenzae meningitis and epiglottitis
  • Treating brain abscesses
  • Treating salmonellosis (typhoid and paratyphoid fever)—use has recently been restricted due to its toxicity
136
Q

What are the adverse effects of chloramphenicol?

A
  • Reversible, dose-related bone marrow depression
  • Aplastic anemia: allergic in nature. Fatal. Non–dose-related
  • Gray-baby syndrome: a fatal toxic reaction. Causes abdominal distension, severe vomiting, cyanosis, hypothermia, respiratory collapse
  • Optic neuritis
  • Nausea
  • Vomiting
  • Diarrhea
137
Q

What is the mechanism of action of spectinomycin?

A

Inhibits protein synthesis

138
Q

What are the features of spectinomycin?

A
  • Bacteriostatic
  • Chemically related to the aminoglycosides
  • Used as an alternative to PCNs and cephalosporins in treating uncomplicated gonococcal infection in patients allergic to those drugs
  • A single IM injection is sufficient
139
Q

What are the tetracyclines?

A
  • Tetracycline
  • Chlortetracycline
  • Oxytetracycline
  • Demeclocycline
  • Doxycycline
  • Minocycline
  • Methacycline
140
Q

What are the properties of tetracyclines?

A
  • Bacteriostatic
  • Have a broad spectrum: antibacterial and antiparasitic
  • Inhibit protein synthesis
  • Somewhat selective since they penetrate the bacterial plasma membrane by an energy-dependent mechanism (which is absent in human cells)
141
Q

How does bacterial resistance to tetracyclines develop?

A
  • Altered bacterial permeability to tetracylcine
  • Increased efflux of tetracyclines by bacterial energy-dependent mechanisms, leading to lower intracellular concentrations
  • Altered structure of bacterial proteins
142
Q

What is the mechanism of action of tetracyclines?

A

Inhibit protein synthesis

143
Q

What are the clinical uses of tetracyclines?

A
  • Effective against Gram-positive and Gram-negative bacteria
  • Considered the drugs of choice in treating Rickettsia, Mycoplasma pneumoniae, and chlamydia
144
Q

What are the pharmacokinetic properties of tetracyclines?

A
  • Doxycycline has the longest duration of action
  • Administration: can be given orally and parentally (as IV)
  • Absorption: food, Mg2+, Al3+, and Ca2+ (especially from milk) form complexes with the drugs and decrease their absorption
  • Distribution: good but do not cross the BBB
  • Excretion: in feces (mino-, oxy-, and chlortetracycline) or urine (the others)
145
Q

What are the adverse effects of tetracyclines?

A
  • Irreversible dental staining (yellowish–brown)
  • Incorporate into growing teeth and bones and are thus contraindicated in pregnant women and children <8 years
  • Nausea, vomiting, diarrhea
  • Hepatotoxicity
  • Photosensitivity (increased sensitivity to sunlight): especially demeclocycline and doxycycline
  • Nephrotoxicity: least with doxycycline and minocycline
  • Increased ICP
  • Superinfection with Candida albicans and Clostridium difficile
146
Q

What are the features of lincomycin and clindamycin?

A
  • Bacteriostatic
  • Inhibitors of bacterial protein synthesis by binding to the 50S subunit and preventing formation of the 70S complex
  • Have good activity against Gram-positive cocci (staphylococci, streptococci), Enterobacteriaceae (Salmonella, Shigella, Klebsiella, Escherichia, Proteus), Vibroaceae (Vibrio cholerae), Pasteurellaceae (Pasteurella, Haemophilus)
  • Have good effect against bone and teeth infections, as well as Corynebacterium acne
147
Q

What are the indications of lincomycin and clindamycin?

A
  • Gram-positive cocci (staphylococci, streptococci)
  • Enterobacteriaceae (Salmonella, Shigella, Klebsiella, Escherichia, Proteus)
  • Vibroaceae (Vibrio cholerae)
  • Pasteurellaceae (Pasteurella, Haemophilus)
  • Bone and teeth infections
  • Corynebacterium acne
148
Q

What are the adverse effects of lincomycin and clindamycin?

A
  • Skin rashes
  • Hepatotoxicity
  • Pseudomembranous colitis (C. difficile)—drug must be stopped and vancomycin ± metronidazole administered
  • Contraindicated in patients with hepatic impairment and a history of pseudomembranous colitis
149
Q

Which antimicrobials are typically administered locally?

A

Polymyxins:

  • Polymixin B
  • Polymixin E (colistin)
150
Q

What are the features of polymyxins?

A
  • Bactericidal
  • Interfere with function or permeability of plasma membrane
  • Effective against Gram-negative bacteria and highly effective against Pseudomonas
151
Q

What are the adverse effects of polymyxins?

A
  • Highly nephrotoxic (even more than the aminoglycosides)
  • Their use is restricted to topical preparations, typically in combination with bacitracin (a cell wall inhibitor) or neomycin, in creams, ointments, eye drops, and ear drops
152
Q

What is the mechanism of action of lincomycin and clindamycin

A

Inhibitors of bacterial protein synthesis by binding to the 50S subunit and preventing formation of the 70S complex

153
Q

What is the mechanism of action of polymyxins

A

Interfere with function or permeability of plasma membrane

154
Q

What are the polymyxins?

A
  • Polymyxin B
  • Polymyxin E (colistin)
155
Q

What are the microbial DNA synthesis inhibitors?

A
  • Quinolones
  • Fluoroquinolones
156
Q

What is the mechanism of action of the quinolones and fluoroquinolones?

A

Inhibition of bacterial DNA gyrase, a type II topoisomerase

157
Q

What are the features of quinolones and fluoroquinolones?

A
  • Inhibitors of bacterial DNA gyrase
  • Bactericidal
  • Chemotherapeutic agents
  • Broad spectrum (effective against pseudomonas)
158
Q

What are the first generation quinolones?

A
  • Nalidixic acid
  • Pipemidic acid
  • Oxolinic acid
159
Q

What are the second generation quinolones?

A
  • Ciprofloxacin
  • Ofloxacin
  • Norfloxacin
  • Enoxacin
  • Lomefloxcin
  • Nadifloxacin
160
Q

What are the third generation quinolones?

A
  • Levofloxacin
  • Sparfloxacin
  • Gatifloxacin
161
Q

What are the fourth generation quinolones?

A
  • Moxifloxacin
  • Prulifloxacin
  • Gemifloxacin
162
Q

What are the clinical uses of the first generation quinolones?

A
  • Most effect in Gram-negative infections and only in UTIs
  • Has little activity against Enterbacteriaceae
  • No effect against pseudomonas
163
Q

What are the clinical uses of the second generation quinolones?

A

More activity against Gram-negative bacteria

164
Q

What are the clinical uses of the third generation quinolones?

A

Good activity against pseudomonas and anaerobic microorganisms

165
Q

Which quinolones are the most widely used?

A
  • Ciprofloxacin (2nd gen)
  • Levofloxacin (3rd gen)
  • Moxifloxacin (4th gen)
166
Q

What are the clinical uses of the quinolones?

A
  • Mainly in complicated UTIs
  • Respiratory infections
  • Invasive external otitis
  • Bacterial prostatitis and cervicitis
  • Bacterial diarrhea caused by Shigella, Salmonella, or E. coli
167
Q

What are the pharmacokinetic properties of the quinolones?

A

Absorption: orally effective and well absorbed but affected by food containing calcium and iron

168
Q

What are the mechanisms of bacterial resistance to quinolones?

A
  • Bacterial efflux pumps decrease intracellular concentrations
  • Some bacteria (especially Gram-negatives) produce proteins that bind to DNA gyrase, protecting it from the action of quinolones
  • Mutations in DNA gyrase/topoisomerase could lead to a decrease in quinolone binding affinity
169
Q

What are the adverse effects of quinolones?

A
  • GI irritation
  • Photosensitivity
  • Cardiac toxicity (many may prolong the QT interval)
  • Some are not recommended in children and during pregnancy as they interfere with cartilage development
  • Some have been reported to be carcinogens
170
Q

What is the mechanism of action of nitrofurantoin?

A

It is converted by bacterial reductases to reactive intermediates that directly damage the bacterial DNA, disrupt RNA transcription and protein synthesis, and interfere with metabolic processes

171
Q

What are the features of nitrofurantoin?

A
  • Synthetic
  • Bactericidal
  • Orally effective
  • Effective against Gram-positive and Gram-negative bacteria (particularly E. coli)
  • Highly effective in UTIs (cystitis), it is known as a UT antiseptic
  • Resistance rarely develops as it has many sites of action
172
Q

What are the adverse effects of nitrofurantoin?

A
  • Pulmonary fibrosis
  • Contraindicated in patients with G6PD deficiency
173
Q

What are the features of fosfomycin?

A
  • A broad-spectrum bactericidal drug
  • Used primarily to treat lower UTIs and occasionally for prostate infections
  • Effective against Gram-positive and Gram-negative organisms and many antibiotic-resistant organisms
174
Q

What is the mechanism of action of fosfomycin?

A

Dirsupts cell wall synthesis by inhibiting phosphoenolpyruvate synthetase, an enzyme in the pathway of peptidoglycan synthesis

175
Q

What are the adverse effects of fosfomycin?

A
  • Restricted to a single dose as resistance builds rapidly
  • Metallic tase
  • Stomach upset
  • Dizziness
  • Stuffy nose
  • Back pain
  • Vaginal itching or discharge
176
Q

What are the features of sulfonamides?

A
  • Broad-spectrum bacteriostatic drugs
  • Structural analogs of PABA used to synthesize dihydrofolate
  • Effective against many Gram-positive and Gram-negative bacteria, nocardia, lymphogranuloma, trachoma, blastomycosis, and many protozoal infections
177
Q

What is the mechanism of action of sulfonamides?

A

Structural analogs of PABA used to synthesize dihydrofolate

178
Q

What are the clinical uses of sulfonamides?

A
  • Upper respiratory tract infections
  • UTIs (sulfamethoxazole, sulfisoxazole)
  • Toxoplasmosis
  • Chlamydia infections
  • Protozoal infections
  • Infected burns
  • Eye infection (sulfacetamide, sufadiazine)
  • Sterilization of the bowel before surgery
  • Sulfasalazine (sulfapyridine salicylate) is used in IBD
179
Q

What are the sulfonamides?

A
  • Sulfamerazine
  • Sulfamethazine
  • Sulfisoxazole
  • Sulfadiazine
  • Sulfacetamide
  • Sulfamethoxazole
  • Phthalylsulfathiazole (sulfathalidine)
  • Sulfasalazine
180
Q

Which sulfonamides are used locally?

A
  • Sulfadiazine
  • Sulfacetamide
181
Q

Which sulfonamides are well absorbed?

A
  • Sulfamerazine
  • Sulfamethazine
  • Sulfisoxazole
  • Sulfadiazine
  • Sulfacetamide
  • Sulfamethoxazole
182
Q

What are the features of sulfamethoxazole?

A
  • The most widely used sulfonamide
  • Well-absorbed
  • Intermediate-acting
183
Q

What are the features of phthalylsuflathiazole?

A
  • Long-acting
  • Orally effective
184
Q

What are the features of sulfasalazine?

A
  • Poorly absorbed from the GI tract
  • Long-acting
185
Q

What are the mechanisms of bacterial resistance to sulfonamides?

A
  • Reduced permeability to the drugs
  • Increased production of PABA
  • Altered dihydropteroate synthase
  • Obtaining reduced folate from the environment
186
Q

What are the pharmacokinetic properties of sulfonamides?

A
  • Distribution: bind plasma proteins (and lead to elevated bilirubin levels in the blood, leading to kernicterus); distributes well, including in the CSF
  • Metabolism: acetylated (metabolites are toxic but inactive)
  • Excretion: renal. They may precipitate in the urine, forming stones, so there must be good fluid intake
187
Q

What are the strategies to avoid precipitation of sulfonamides in the urine?

A
  • Good fluid intake
  • Using sulfisoxazole, which has high urine solubility
  • Using combined sulfa drugs at lower total doses (due to synergism)
  • Alkalization of the urine
188
Q

What are the features of trimethoprim?

A
  • Bacteriostatic
  • A structural analog of folic acid
  • Inhibits dihydrofolate reductase
  • Effective against E. coli, H. influenzae, K. pneumoniae
  • Ineffective against pseudomonas and Proteus
  • Used in the treatment and prophylaxis of UTIs
189
Q

How do the pharmacokinetic properties of trimethoprim compare to those of the sulfonamides?

A
  • Faster onset of action
  • Well absorbed orally, like the sulfonamides
  • Has a similar half-life to sulfamethoxazole
  • Crosses the BBB to a lesser extent
  • Excreted unchanged in the kidney
  • Associated with fewer side effects
190
Q

Which sulfonamide is commonly combined with trimethoprim?

A

Sulfamethoxazole (co-trimoxazole)

191
Q

What are the properties of combined sulfamethoxazole–trimethoprim (co-trimoxazole)?

A
  • Acts sequentially in preventing nucleic acid synthesis in some bacteria
  • Synergistic activity
  • Broader spectrum but still not effective against pseudomonas
  • More bactericidal
  • Resistance is less likely
192
Q

What are the adverse effects of sulfonamides?

A
  • Allergic reactions (frequent)
  • Kernicterus
  • Renal damage (toxic nephrosis, allergic nephritis, drug crystals)
  • Liver damage (rare)
  • Nausea
  • Vomiting
  • Blood dyscrasia, hemolysis in G6PD deficient patients
  • Steven-Johnson syndrome (uncommon): inflammatory condition of the skin and mucosal membranes

Pharmacology (2 decks)

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