Drugs for infections

Drugs for infections

Drugs used for infections include antibacterials, antifungals, antivirals, antimycobacterials and antiparasitic drugs.

Antibacterials which act to kill or inhibit the growth of bacteria, target essential bacterial molecular pathways not shared with the host (e.g. inhibiting nucleic acid precursor synthesis, protein synthesis, and cell membrane integrity). Antifungal drugs utilize similar mechanisms, targeting fungal cell wall-synthesizing enzymes for example. The machinery of viral replication are targets for antiviral drugs including HIV, and drugs used in treating mycobacterial infections represent another spectrum of action of drugs for infections.

 

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Introduction to Antimicrobials

Antibacterial drugs may be grouped according to how they alter bacterial cell function/structure, e.g.

  • nucleic acid precursor synthesis;
  • DNA replication and structure;
  • protein synthesis;
  • cell wall peptidoglycan synthesis;
  • cell membrane integrity

Class II & III reactions in the bacteria are targets for antibacterial drugs since these reactions are unique in bacterial cells. Class II reactions include those responsible for synthesis of molecular building blocks (i.e. precursors of DNA, proteins, etc.). Bacteria rely on synthesis of folate by themselves rather than intake from other sources. Thus, interference with the folate biosynthesis pathway is one mechanism employed by antibacterial drugs. Class III reactions make use of the aforementioned building blocks to replicate DNA, synthesise proteins and cell wall components and maintain cell membrane structure. Mechanisms involved are very different between humans and bacteria, thereby favouring the actions of many antibacterial drugs.

Mechanisms and Classification of Antibiotics

Part of this video (from 5:14 to 8:05), describes different classes of antibiotics with their sites and mechanisms of actions briefly introduced.  This information is useful for the learner to gain an understanding of the different modes of antibacterial drug actions.

Beginner level

Author: Eric Strong/ Strong Medicine

Average: 3.1 (8 votes)

Aminoglycosides

Aminoglycosides are bactericidal in function, and are named after the amino-modified glycoside (sugar) that is part of their chemical structure. The primary mode of action of aminoglycosides is by inhibition of protein synthesis. Commonly-used drugs in this class include amikacin, gentamicin, neomycin sulfate, streptomycin, and tobramycin. All are bactericidal and active against some Gram-positive and many Gram-negative organisms. Amikacin, gentamicin, and tobramycin are also active against Pseudomonas aeruginosa. Streptomycin is active against Mycobacterium tuberculosis and is now almost entirely reserved for tuberculosis.

Aminoglycosides

This short video (7:11) is part of an introductory series of videos on antibiotic classes produced by Ryan Sheehy of Kansas City University. It uses a narrated animation to introduce you to the basic structure, mechanisms of action and clinical uses of aminoglycosides. Aminoglycosides act by inhibiting bacterial protein synthesis.

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Cephalosporins

Cephalosporins are a class of β-lactam antibiotics derived from the fungus Cephalosporium.  This class of antibiotics works by inhibiting bacterial cell wall synthesis by binding to penicillin binding proteins, causing bacterial cell lysis.  Specific examples of penicillin binding proteins include carboxypeptidases and endopeptidases; these penicillin binding protein enzymes normally form the peptide cross links between peptidoglycans in bacterial cell walls.  However, in the presence of beta-lactam antibiotics, formation of these cross-links is disrupted, the cell wall becomes osmotically unstable, and bacteria burst from osmotic pressure.  Cephalosporins are both bactericidal and time dependent, meaning that they effectively kill susceptible bacteria as long as the plasma concentration of the antibiotic remains above the minimum inhibitory concentration between doses. 

The structures of the agents in this class vary greatly, but they generally share commonalities around a β-lactam ring (e.g. the “square” four membered ring).  In the figure, the functional group R2 determines both the anti-bacterial spectrum coverage and β-lactamase resistance, while R1 determines metabolism and pharmacokinetic parameters of the cephalosporin.

These drugs are renally eliminated and doses must be adjusted when renal dysfunction is present.  The most common adverse reactions to cephalosporins are gastrointestinal upset and an allergic reaction in the form of a rash.  Due to their structural similarities with penicillins, there is a slight chance individuals with penicillin allergies may experience cross-reactivity with cephalosporins.  What was once thought to be a 10% risk of cross-reactivity is now thought to be attributed to cross-contamination during manufacturing processes and is now believed to be closer to 1% with first generation cephalosporins and less likely with other generations.  The third and fourth generation cephalosporins have side chains that generally render them dissimilar enough to penicillins so as to not lead to cross-sensitivity; thus, individuals with a history of hives to penicillins can usually tolerate the newer cephalosporins without any problems.  However, to be on the safe side, in general, all cephalosporins are usually avoided in individuals that report a history of anaphylactic reactions to penicillins.

Resistance to cephalosporins arises via two different mechanisms.  Target-mediated resistance occurs when bacteria have alterations in penicillin binding proteins that reduce a cephalosporin’s affinity for binding to penicillin binding proteins.  Another mechanism of resistance occurs if the bacteria acquire β-lactamase enzymes, known as cephalosporinases, capable of lysing and opening the β-lactam ring, rendering the molecule inactive. 

There are various cephalosporins available on the market today.  They are commonly divided into different groups, called generations, based on the structure of their side chains, and thus their antimicrobial activities.

 

1st Generation Cephalosporins

First generation cephalosporins have good activity against gram-positive bacteria including penicillinase-producing streptococci and staphylococci and modest activity against gram-negative rods such as K. pneumonia, P. mirabilis, and E. coli.  However, they offer no reliable anaerobic coverage.   They, along with some penicillins, are often drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA).  Agents in this class include cephalexin, cefazolin, and cefadroxil.  Cephalexin is often used orally to treat skin infections and cellulitis. Cefazolin is commonly administered during surgery to prevent infections of the surgical site.    Chemically, cefazolin contains a N-methyl thiotetrazole (NMTT) functional group which has been linked to specific adverse effects.  Specifically, when alcohol is consumed, a disulfiram-like reaction characterized by unpleasant side effects like severe nausea and vomiting can occur when drugs with NMTT side chains are taken.  The NMTT chemical ring also interferes with vitamin K formation and can lead to an increased bleeding risk in some patients. 

 

2nd Generation Cephalosporins

Second generation agents include cefuroxime, cefoxitin, cefotetan, cefprozil, and cefaclor.  As a group, the second generation cephalosporins sacrifice some activity against gram-positive bacteria in favor of gaining more gram-negative coverage.  These drugs possess gram-negative coverage for H. influenza and M. catarrhalis, organisms that commonly cause upper respiratory tract infections as well as coverage for E. coli and other gram negative bacteria that cause uncomplicated urinary tract infections.  The drugs cefoxitin and cefotetan have added benefits of possessing anaerobic coverage for B. fragilis, a cause of intra-abdominal infections.  Cefotetan also has the NMTT functional group mentioned above with cefazolin and may produce a disulfiram-like reaction if alcohol is consumed; this side chain may also increase bleeding risk.  Cefaclor has been associated with a non-allergic rash caused by reactive intermediates that acetylate proteins and produce immunogenic complexes; however, this reaction is not a contraindication to use of other cephalosporins or penicillins.

 

3rd Generation Cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefixime, cefpodoxime, cefdinir, and ceftibuten are considered third generation cephalosporins.  Third generation cephalosporins cannot be used to treat staphylococcal or anaerobic infections, but do possess coverage against pneumococcal organisms.  Furthermore, third generation cephalosporins exhibit enhanced gram-negative activity and are useful for treating infections caused by Enterobacteriaceae, Serratia spp., and N. gonorrhea.  Ceftriaxone is often used to treat serious community-acquired pneumonia infections, but since it does not cover pseudomonas, it is not be an appropriate choice for health-care acquired pneumonia.   On the other hand, ceftazidime is a drug of choice for treating infections caused by P. aeruginosa including lung infections.  In the presence of central nervous system inflammation, ceftriaxone and cefotaxime can cross the blood brain barrier and can be used in combination with other drugs to treat meningitis.  Although most third generation drugs are eliminated predominantly by the kidneys, ceftriaxone has dual elimination with the kidneys and liver and can cause pseudocholelithiasis, which is a feeling like a person has a gall stone -- a situation that usually resolves after the medication is stopped.  In addition, ceftriaxone can precipitate in the gall bladder and lead to stone formation; in attempt to avoid this, the drug should never be administered with intravenous calcium.  Due to their relatively broad spectrum against normal gut bacterial flora, the agents in this generation are commonly implicated in causing C. difficile-associated diarrhea.

4th Generation Cephalosporin

Cefepime is considered to be a fourth generation cephalosporin.  It combines the gram-positive coverage of the first generation cephalosporins with the gram-negative coverage of the third generation cephalosporins.  Like ceftazidime of the third generation agents, cefepime lacks anaerobic coverage but is active against P. aeruginosa.  It is the broadest spectrum cephalosporin and is the drug of choice for Enterobacter spp.  Its use is often reserved for empiric treatment in hospitalized patients when coverage for gram-positive organisms, Enterobacteriaceae, or Pseudomonas spp is needed.

Rebecca Kramer, Kelly Karpa

ß-Lactams: Mechanisms of Action and Resistance

This 7 minute video showcases bacterial cell wall synthesis, the mechanism of action of cephalosporins (starting at 2:33), and the mechanisms by which bacteria develop resistance to cephalosporins (starting at 3:38). 

Intermediate level.

Author: Mechanisms in Medicine

No votes yet

Cephalosporins are a class of β-lactam antibiotics derived from the fungus Cephalosporium.  This class of antibiotics works by inhibiting bacterial cell wall synthesis by binding to penicillin binding proteins, causing bacterial cell lysis.  Specific examples of penicillin binding proteins include carboxypeptidases and endopeptidases; these penicillin binding protein enzymes normally form the peptide cross links between peptidoglycans in bacterial cell walls.  However, in the presence of beta-lactam antibiotics, formation of these cross-links is disrupted, the cell wall becomes osmotically unstable, and bacteria burst from osmotic pressure.  Cephalosporins are both bactericidal and time dependent, meaning that they effectively kill susceptible bacteria as long as the plasma concentration of the antibiotic remains above the minimum inhibitory concentration between doses. 

The structures of the agents in this class vary greatly, but they generally share commonalities around a β-lactam ring (e.g. the “square” four membered ring).  In the figure, the functional group R2 determines both the anti-bacterial spectrum coverage and β-lactamase resistance, while R1 determines metabolism and pharmacokinetic parameters of the cephalosporin.

These drugs are renally eliminated and doses must be adjusted when renal dysfunction is present.  The most common adverse reactions to cephalosporins are gastrointestinal upset and an allergic reaction in the form of a rash.  Due to their structural similarities with penicillins, there is a slight chance individuals with penicillin allergies may experience cross-reactivity with cephalosporins.  What was once thought to be a 10% risk of cross-reactivity is now thought to be attributed to cross-contamination during manufacturing processes and is now believed to be closer to 1% with first generation cephalosporins and less likely with other generations.  The third and fourth generation cephalosporins have side chains that generally render them dissimilar enough to penicillins so as to not lead to cross-sensitivity; thus, individuals with a history of hives to penicillins can usually tolerate the newer cephalosporins without any problems.  However, to be on the safe side, in general, all cephalosporins are usually avoided in individuals that report a history of anaphylactic reactions to penicillins.

Resistance to cephalosporins arises via two different mechanisms.  Target-mediated resistance occurs when bacteria have alterations in penicillin binding proteins that reduce a cephalosporin’s affinity for binding to penicillin binding proteins.  Another mechanism of resistance occurs if the bacteria acquire β-lactamase enzymes, known as cephalosporinases, capable of lysing and opening the β-lactam ring, rendering the molecule inactive. 

There are various cephalosporins available on the market today.  They are commonly divided into different groups, called generations, based on the structure of their side chains, and thus their antimicrobial activities.

 

1st Generation Cephalosporins

First generation cephalosporins have good activity against gram-positive bacteria including penicillinase-producing streptococci and staphylococci and modest activity against gram-negative rods such as K. pneumonia, P. mirabilis, and E. coli.  However, they offer no reliable anaerobic coverage.   They, along with some penicillins, are often drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA).  Agents in this class include cephalexin, cefazolin, and cefadroxil.  Cephalexin is often used orally to treat skin infections and cellulitis. Cefazolin is commonly administered during surgery to prevent infections of the surgical site.    Chemically, cefazolin contains a N-methyl thiotetrazole (NMTT) functional group which has been linked to specific adverse effects.  Specifically, when alcohol is consumed, a disulfiram-like reaction characterized by unpleasant side effects like severe nausea and vomiting can occur when drugs with NMTT side chains are taken.  The NMTT chemical ring also interferes with vitamin K formation and can lead to an increased bleeding risk in some patients. 

 

2nd Generation Cephalosporins

Second generation agents include cefuroxime, cefoxitin, cefotetan, cefprozil, and cefaclor.  As a group, the second generation cephalosporins sacrifice some activity against gram-positive bacteria in favor of gaining more gram-negative coverage.  These drugs possess gram-negative coverage for H. influenza and M. catarrhalis, organisms that commonly cause upper respiratory tract infections as well as coverage for E. coli and other gram negative bacteria that cause uncomplicated urinary tract infections.  The drugs cefoxitin and cefotetan have added benefits of possessing anaerobic coverage for B. fragilis, a cause of intra-abdominal infections.  Cefotetan also has the NMTT functional group mentioned above with cefazolin and may produce a disulfiram-like reaction if alcohol is consumed; this side chain may also increase bleeding risk.  Cefaclor has been associated with a non-allergic rash caused by reactive intermediates that acetylate proteins and produce immunogenic complexes; however, this reaction is not a contraindication to use of other cephalosporins or penicillins.

 

3rd Generation Cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefixime, cefpodoxime, cefdinir, and ceftibuten are considered third generation cephalosporins.  Third generation cephalosporins cannot be used to treat staphylococcal or anaerobic infections, but do possess coverage against pneumococcal organisms.  Furthermore, third generation cephalosporins exhibit enhanced gram-negative activity and are useful for treating infections caused by Enterobacteriaceae, Serratia spp., and N. gonorrhea.  Ceftriaxone is often used to treat serious community-acquired pneumonia infections, but since it does not cover pseudomonas, it is not be an appropriate choice for health-care acquired pneumonia.   On the other hand, ceftazidime is a drug of choice for treating infections caused by P. aeruginosa including lung infections.  In the presence of central nervous system inflammation, ceftriaxone and cefotaxime can cross the blood brain barrier and can be used in combination with other drugs to treat meningitis.  Although most third generation drugs are eliminated predominantly by the kidneys, ceftriaxone has dual elimination with the kidneys and liver and can cause pseudocholelithiasis, which is a feeling like a person has a gall stone -- a situation that usually resolves after the medication is stopped.  In addition, ceftriaxone can precipitate in the gall bladder and lead to stone formation; in attempt to avoid this, the drug should never be administered with intravenous calcium.  Due to their relatively broad spectrum against normal gut bacterial flora, the agents in this generation are commonly implicated in causing C. difficile-associated diarrhea.

4th Generation Cephalosporin

Cefepime is considered to be a fourth generation cephalosporin.  It combines the gram-positive coverage of the first generation cephalosporins with the gram-negative coverage of the third generation cephalosporins.  Like ceftazidime of the third generation agents, cefepime lacks anaerobic coverage but is active against P. aeruginosa.  It is the broadest spectrum cephalosporin and is the drug of choice for Enterobacter spp.  Its use is often reserved for empiric treatment in hospitalized patients when coverage for gram-positive organisms, Enterobacteriaceae, or Pseudomonas spp is needed.

Rebecca Kramer, Kelly Karpa

Cephalosporins resource; eMedExpert

This article provides a more in-depth overview of cephalosporins, broken down by their generation.  Their mechanism of action, adverse effects, spectrum of activity, and clinical use are discussed in detail.  It also provides resources for further reading on cephalosporins. 

Intermediate level.

Author: eMedExpert

No votes yet

Cephalosporins are a class of β-lactam antibiotics derived from the fungus Cephalosporium.  This class of antibiotics works by inhibiting bacterial cell wall synthesis by binding to penicillin binding proteins, causing bacterial cell lysis.  Specific examples of penicillin binding proteins include carboxypeptidases and endopeptidases; these penicillin binding protein enzymes normally form the peptide cross links between peptidoglycans in bacterial cell walls.  However, in the presence of beta-lactam antibiotics, formation of these cross-links is disrupted, the cell wall becomes osmotically unstable, and bacteria burst from osmotic pressure.  Cephalosporins are both bactericidal and time dependent, meaning that they effectively kill susceptible bacteria as long as the plasma concentration of the antibiotic remains above the minimum inhibitory concentration between doses. 

The structures of the agents in this class vary greatly, but they generally share commonalities around a β-lactam ring (e.g. the “square” four membered ring).  In the figure, the functional group R2 determines both the anti-bacterial spectrum coverage and β-lactamase resistance, while R1 determines metabolism and pharmacokinetic parameters of the cephalosporin.

These drugs are renally eliminated and doses must be adjusted when renal dysfunction is present.  The most common adverse reactions to cephalosporins are gastrointestinal upset and an allergic reaction in the form of a rash.  Due to their structural similarities with penicillins, there is a slight chance individuals with penicillin allergies may experience cross-reactivity with cephalosporins.  What was once thought to be a 10% risk of cross-reactivity is now thought to be attributed to cross-contamination during manufacturing processes and is now believed to be closer to 1% with first generation cephalosporins and less likely with other generations.  The third and fourth generation cephalosporins have side chains that generally render them dissimilar enough to penicillins so as to not lead to cross-sensitivity; thus, individuals with a history of hives to penicillins can usually tolerate the newer cephalosporins without any problems.  However, to be on the safe side, in general, all cephalosporins are usually avoided in individuals that report a history of anaphylactic reactions to penicillins.

Resistance to cephalosporins arises via two different mechanisms.  Target-mediated resistance occurs when bacteria have alterations in penicillin binding proteins that reduce a cephalosporin’s affinity for binding to penicillin binding proteins.  Another mechanism of resistance occurs if the bacteria acquire β-lactamase enzymes, known as cephalosporinases, capable of lysing and opening the β-lactam ring, rendering the molecule inactive. 

There are various cephalosporins available on the market today.  They are commonly divided into different groups, called generations, based on the structure of their side chains, and thus their antimicrobial activities.

 

1st Generation Cephalosporins

First generation cephalosporins have good activity against gram-positive bacteria including penicillinase-producing streptococci and staphylococci and modest activity against gram-negative rods such as K. pneumonia, P. mirabilis, and E. coli.  However, they offer no reliable anaerobic coverage.   They, along with some penicillins, are often drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA).  Agents in this class include cephalexin, cefazolin, and cefadroxil.  Cephalexin is often used orally to treat skin infections and cellulitis. Cefazolin is commonly administered during surgery to prevent infections of the surgical site.    Chemically, cefazolin contains a N-methyl thiotetrazole (NMTT) functional group which has been linked to specific adverse effects.  Specifically, when alcohol is consumed, a disulfiram-like reaction characterized by unpleasant side effects like severe nausea and vomiting can occur when drugs with NMTT side chains are taken.  The NMTT chemical ring also interferes with vitamin K formation and can lead to an increased bleeding risk in some patients. 

 

2nd Generation Cephalosporins

Second generation agents include cefuroxime, cefoxitin, cefotetan, cefprozil, and cefaclor.  As a group, the second generation cephalosporins sacrifice some activity against gram-positive bacteria in favor of gaining more gram-negative coverage.  These drugs possess gram-negative coverage for H. influenza and M. catarrhalis, organisms that commonly cause upper respiratory tract infections as well as coverage for E. coli and other gram negative bacteria that cause uncomplicated urinary tract infections.  The drugs cefoxitin and cefotetan have added benefits of possessing anaerobic coverage for B. fragilis, a cause of intra-abdominal infections.  Cefotetan also has the NMTT functional group mentioned above with cefazolin and may produce a disulfiram-like reaction if alcohol is consumed; this side chain may also increase bleeding risk.  Cefaclor has been associated with a non-allergic rash caused by reactive intermediates that acetylate proteins and produce immunogenic complexes; however, this reaction is not a contraindication to use of other cephalosporins or penicillins.

 

3rd Generation Cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefixime, cefpodoxime, cefdinir, and ceftibuten are considered third generation cephalosporins.  Third generation cephalosporins cannot be used to treat staphylococcal or anaerobic infections, but do possess coverage against pneumococcal organisms.  Furthermore, third generation cephalosporins exhibit enhanced gram-negative activity and are useful for treating infections caused by Enterobacteriaceae, Serratia spp., and N. gonorrhea.  Ceftriaxone is often used to treat serious community-acquired pneumonia infections, but since it does not cover pseudomonas, it is not be an appropriate choice for health-care acquired pneumonia.   On the other hand, ceftazidime is a drug of choice for treating infections caused by P. aeruginosa including lung infections.  In the presence of central nervous system inflammation, ceftriaxone and cefotaxime can cross the blood brain barrier and can be used in combination with other drugs to treat meningitis.  Although most third generation drugs are eliminated predominantly by the kidneys, ceftriaxone has dual elimination with the kidneys and liver and can cause pseudocholelithiasis, which is a feeling like a person has a gall stone -- a situation that usually resolves after the medication is stopped.  In addition, ceftriaxone can precipitate in the gall bladder and lead to stone formation; in attempt to avoid this, the drug should never be administered with intravenous calcium.  Due to their relatively broad spectrum against normal gut bacterial flora, the agents in this generation are commonly implicated in causing C. difficile-associated diarrhea.

4th Generation Cephalosporin

Cefepime is considered to be a fourth generation cephalosporin.  It combines the gram-positive coverage of the first generation cephalosporins with the gram-negative coverage of the third generation cephalosporins.  Like ceftazidime of the third generation agents, cefepime lacks anaerobic coverage but is active against P. aeruginosa.  It is the broadest spectrum cephalosporin and is the drug of choice for Enterobacter spp.  Its use is often reserved for empiric treatment in hospitalized patients when coverage for gram-positive organisms, Enterobacteriaceae, or Pseudomonas spp is needed.

Rebecca Kramer, Kelly Karpa

Cephalosporins Clearly Explained

This 12 minute video discusses cephalosporins by generation, including spectrum coverage and clinical uses.

Beginner level.

Author: Roger Seheult, MD

No votes yet

Cephalosporins are a class of β-lactam antibiotics derived from the fungus Cephalosporium.  This class of antibiotics works by inhibiting bacterial cell wall synthesis by binding to penicillin binding proteins, causing bacterial cell lysis.  Specific examples of penicillin binding proteins include carboxypeptidases and endopeptidases; these penicillin binding protein enzymes normally form the peptide cross links between peptidoglycans in bacterial cell walls.  However, in the presence of beta-lactam antibiotics, formation of these cross-links is disrupted, the cell wall becomes osmotically unstable, and bacteria burst from osmotic pressure.  Cephalosporins are both bactericidal and time dependent, meaning that they effectively kill susceptible bacteria as long as the plasma concentration of the antibiotic remains above the minimum inhibitory concentration between doses. 

The structures of the agents in this class vary greatly, but they generally share commonalities around a β-lactam ring (e.g. the “square” four membered ring).  In the figure, the functional group R2 determines both the anti-bacterial spectrum coverage and β-lactamase resistance, while R1 determines metabolism and pharmacokinetic parameters of the cephalosporin.

These drugs are renally eliminated and doses must be adjusted when renal dysfunction is present.  The most common adverse reactions to cephalosporins are gastrointestinal upset and an allergic reaction in the form of a rash.  Due to their structural similarities with penicillins, there is a slight chance individuals with penicillin allergies may experience cross-reactivity with cephalosporins.  What was once thought to be a 10% risk of cross-reactivity is now thought to be attributed to cross-contamination during manufacturing processes and is now believed to be closer to 1% with first generation cephalosporins and less likely with other generations.  The third and fourth generation cephalosporins have side chains that generally render them dissimilar enough to penicillins so as to not lead to cross-sensitivity; thus, individuals with a history of hives to penicillins can usually tolerate the newer cephalosporins without any problems.  However, to be on the safe side, in general, all cephalosporins are usually avoided in individuals that report a history of anaphylactic reactions to penicillins.

Resistance to cephalosporins arises via two different mechanisms.  Target-mediated resistance occurs when bacteria have alterations in penicillin binding proteins that reduce a cephalosporin’s affinity for binding to penicillin binding proteins.  Another mechanism of resistance occurs if the bacteria acquire β-lactamase enzymes, known as cephalosporinases, capable of lysing and opening the β-lactam ring, rendering the molecule inactive. 

There are various cephalosporins available on the market today.  They are commonly divided into different groups, called generations, based on the structure of their side chains, and thus their antimicrobial activities.

 

1st Generation Cephalosporins

First generation cephalosporins have good activity against gram-positive bacteria including penicillinase-producing streptococci and staphylococci and modest activity against gram-negative rods such as K. pneumonia, P. mirabilis, and E. coli.  However, they offer no reliable anaerobic coverage.   They, along with some penicillins, are often drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA).  Agents in this class include cephalexin, cefazolin, and cefadroxil.  Cephalexin is often used orally to treat skin infections and cellulitis. Cefazolin is commonly administered during surgery to prevent infections of the surgical site.    Chemically, cefazolin contains a N-methyl thiotetrazole (NMTT) functional group which has been linked to specific adverse effects.  Specifically, when alcohol is consumed, a disulfiram-like reaction characterized by unpleasant side effects like severe nausea and vomiting can occur when drugs with NMTT side chains are taken.  The NMTT chemical ring also interferes with vitamin K formation and can lead to an increased bleeding risk in some patients. 

 

2nd Generation Cephalosporins

Second generation agents include cefuroxime, cefoxitin, cefotetan, cefprozil, and cefaclor.  As a group, the second generation cephalosporins sacrifice some activity against gram-positive bacteria in favor of gaining more gram-negative coverage.  These drugs possess gram-negative coverage for H. influenza and M. catarrhalis, organisms that commonly cause upper respiratory tract infections as well as coverage for E. coli and other gram negative bacteria that cause uncomplicated urinary tract infections.  The drugs cefoxitin and cefotetan have added benefits of possessing anaerobic coverage for B. fragilis, a cause of intra-abdominal infections.  Cefotetan also has the NMTT functional group mentioned above with cefazolin and may produce a disulfiram-like reaction if alcohol is consumed; this side chain may also increase bleeding risk.  Cefaclor has been associated with a non-allergic rash caused by reactive intermediates that acetylate proteins and produce immunogenic complexes; however, this reaction is not a contraindication to use of other cephalosporins or penicillins.

 

3rd Generation Cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefixime, cefpodoxime, cefdinir, and ceftibuten are considered third generation cephalosporins.  Third generation cephalosporins cannot be used to treat staphylococcal or anaerobic infections, but do possess coverage against pneumococcal organisms.  Furthermore, third generation cephalosporins exhibit enhanced gram-negative activity and are useful for treating infections caused by Enterobacteriaceae, Serratia spp., and N. gonorrhea.  Ceftriaxone is often used to treat serious community-acquired pneumonia infections, but since it does not cover pseudomonas, it is not be an appropriate choice for health-care acquired pneumonia.   On the other hand, ceftazidime is a drug of choice for treating infections caused by P. aeruginosa including lung infections.  In the presence of central nervous system inflammation, ceftriaxone and cefotaxime can cross the blood brain barrier and can be used in combination with other drugs to treat meningitis.  Although most third generation drugs are eliminated predominantly by the kidneys, ceftriaxone has dual elimination with the kidneys and liver and can cause pseudocholelithiasis, which is a feeling like a person has a gall stone -- a situation that usually resolves after the medication is stopped.  In addition, ceftriaxone can precipitate in the gall bladder and lead to stone formation; in attempt to avoid this, the drug should never be administered with intravenous calcium.  Due to their relatively broad spectrum against normal gut bacterial flora, the agents in this generation are commonly implicated in causing C. difficile-associated diarrhea.

4th Generation Cephalosporin

Cefepime is considered to be a fourth generation cephalosporin.  It combines the gram-positive coverage of the first generation cephalosporins with the gram-negative coverage of the third generation cephalosporins.  Like ceftazidime of the third generation agents, cefepime lacks anaerobic coverage but is active against P. aeruginosa.  It is the broadest spectrum cephalosporin and is the drug of choice for Enterobacter spp.  Its use is often reserved for empiric treatment in hospitalized patients when coverage for gram-positive organisms, Enterobacteriaceae, or Pseudomonas spp is needed.

Rebecca Kramer, Kelly Karpa

Antibiotics- Cephalosporins; iMedicalSchool

This 9.5-minute video discusses cephalosporins by generation and individual agents, as well as spectrum of coverage and clinical uses.

Beginner level.

Author: iMedicalSchool

No votes yet

Cephalosporins are a class of β-lactam antibiotics derived from the fungus Cephalosporium.  This class of antibiotics works by inhibiting bacterial cell wall synthesis by binding to penicillin binding proteins, causing bacterial cell lysis.  Specific examples of penicillin binding proteins include carboxypeptidases and endopeptidases; these penicillin binding protein enzymes normally form the peptide cross links between peptidoglycans in bacterial cell walls.  However, in the presence of beta-lactam antibiotics, formation of these cross-links is disrupted, the cell wall becomes osmotically unstable, and bacteria burst from osmotic pressure.  Cephalosporins are both bactericidal and time dependent, meaning that they effectively kill susceptible bacteria as long as the plasma concentration of the antibiotic remains above the minimum inhibitory concentration between doses. 

The structures of the agents in this class vary greatly, but they generally share commonalities around a β-lactam ring (e.g. the “square” four membered ring).  In the figure, the functional group R2 determines both the anti-bacterial spectrum coverage and β-lactamase resistance, while R1 determines metabolism and pharmacokinetic parameters of the cephalosporin.

These drugs are renally eliminated and doses must be adjusted when renal dysfunction is present.  The most common adverse reactions to cephalosporins are gastrointestinal upset and an allergic reaction in the form of a rash.  Due to their structural similarities with penicillins, there is a slight chance individuals with penicillin allergies may experience cross-reactivity with cephalosporins.  What was once thought to be a 10% risk of cross-reactivity is now thought to be attributed to cross-contamination during manufacturing processes and is now believed to be closer to 1% with first generation cephalosporins and less likely with other generations.  The third and fourth generation cephalosporins have side chains that generally render them dissimilar enough to penicillins so as to not lead to cross-sensitivity; thus, individuals with a history of hives to penicillins can usually tolerate the newer cephalosporins without any problems.  However, to be on the safe side, in general, all cephalosporins are usually avoided in individuals that report a history of anaphylactic reactions to penicillins.

Resistance to cephalosporins arises via two different mechanisms.  Target-mediated resistance occurs when bacteria have alterations in penicillin binding proteins that reduce a cephalosporin’s affinity for binding to penicillin binding proteins.  Another mechanism of resistance occurs if the bacteria acquire β-lactamase enzymes, known as cephalosporinases, capable of lysing and opening the β-lactam ring, rendering the molecule inactive. 

There are various cephalosporins available on the market today.  They are commonly divided into different groups, called generations, based on the structure of their side chains, and thus their antimicrobial activities.

 

1st Generation Cephalosporins

First generation cephalosporins have good activity against gram-positive bacteria including penicillinase-producing streptococci and staphylococci and modest activity against gram-negative rods such as K. pneumonia, P. mirabilis, and E. coli.  However, they offer no reliable anaerobic coverage.   They, along with some penicillins, are often drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA).  Agents in this class include cephalexin, cefazolin, and cefadroxil.  Cephalexin is often used orally to treat skin infections and cellulitis. Cefazolin is commonly administered during surgery to prevent infections of the surgical site.    Chemically, cefazolin contains a N-methyl thiotetrazole (NMTT) functional group which has been linked to specific adverse effects.  Specifically, when alcohol is consumed, a disulfiram-like reaction characterized by unpleasant side effects like severe nausea and vomiting can occur when drugs with NMTT side chains are taken.  The NMTT chemical ring also interferes with vitamin K formation and can lead to an increased bleeding risk in some patients. 

 

2nd Generation Cephalosporins

Second generation agents include cefuroxime, cefoxitin, cefotetan, cefprozil, and cefaclor.  As a group, the second generation cephalosporins sacrifice some activity against gram-positive bacteria in favor of gaining more gram-negative coverage.  These drugs possess gram-negative coverage for H. influenza and M. catarrhalis, organisms that commonly cause upper respiratory tract infections as well as coverage for E. coli and other gram negative bacteria that cause uncomplicated urinary tract infections.  The drugs cefoxitin and cefotetan have added benefits of possessing anaerobic coverage for B. fragilis, a cause of intra-abdominal infections.  Cefotetan also has the NMTT functional group mentioned above with cefazolin and may produce a disulfiram-like reaction if alcohol is consumed; this side chain may also increase bleeding risk.  Cefaclor has been associated with a non-allergic rash caused by reactive intermediates that acetylate proteins and produce immunogenic complexes; however, this reaction is not a contraindication to use of other cephalosporins or penicillins.

 

3rd Generation Cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefixime, cefpodoxime, cefdinir, and ceftibuten are considered third generation cephalosporins.  Third generation cephalosporins cannot be used to treat staphylococcal or anaerobic infections, but do possess coverage against pneumococcal organisms.  Furthermore, third generation cephalosporins exhibit enhanced gram-negative activity and are useful for treating infections caused by Enterobacteriaceae, Serratia spp., and N. gonorrhea.  Ceftriaxone is often used to treat serious community-acquired pneumonia infections, but since it does not cover pseudomonas, it is not be an appropriate choice for health-care acquired pneumonia.   On the other hand, ceftazidime is a drug of choice for treating infections caused by P. aeruginosa including lung infections.  In the presence of central nervous system inflammation, ceftriaxone and cefotaxime can cross the blood brain barrier and can be used in combination with other drugs to treat meningitis.  Although most third generation drugs are eliminated predominantly by the kidneys, ceftriaxone has dual elimination with the kidneys and liver and can cause pseudocholelithiasis, which is a feeling like a person has a gall stone -- a situation that usually resolves after the medication is stopped.  In addition, ceftriaxone can precipitate in the gall bladder and lead to stone formation; in attempt to avoid this, the drug should never be administered with intravenous calcium.  Due to their relatively broad spectrum against normal gut bacterial flora, the agents in this generation are commonly implicated in causing C. difficile-associated diarrhea.

4th Generation Cephalosporin

Cefepime is considered to be a fourth generation cephalosporin.  It combines the gram-positive coverage of the first generation cephalosporins with the gram-negative coverage of the third generation cephalosporins.  Like ceftazidime of the third generation agents, cefepime lacks anaerobic coverage but is active against P. aeruginosa.  It is the broadest spectrum cephalosporin and is the drug of choice for Enterobacter spp.  Its use is often reserved for empiric treatment in hospitalized patients when coverage for gram-positive organisms, Enterobacteriaceae, or Pseudomonas spp is needed.

Rebecca Kramer, Kelly Karpa

First Generation Cephalosporins

This learning resource includes links to a set of short videos (all <4 minutes) that are part of an introductory series of videos on antibiotic classes produced by Ryan Sheehy of Kansas City University. They use narrated animation to introduce you to the basic structure, mechanisms of action and resistance, spectrum and adverse effects of the evolving generations cephalosporins.

The 1st generation cephalosporins (including cefazolin and cephalexin among others) inhibit transpeptidase and cell wall synthesis similar the other cephalosporins. The drugs in this generation are active against gram-positive cocci except MRSA, enterococci and Staphylococcus epidermidis. They have modest activity against gram-negative bacteria. The introductory video on cephalosporins (https://www.youtube.com/watch?v=FBnvhZT2TXo) should be viewed before watching these videos.

Second generation cephalosporins

The 2nd generation cephalosporins include cefuroxime, cefaclor, and cefprozil, and the cephamycins cefoxitin and cefotetan among others. This group are generally active against the same organisms as the 1st generation drugs but have expanded gram-negative coverage.

Third generation cephalosporins

The 3rd generation cephalosporins (including cefoxatime and ceftriaxone among others) are more active against gram-negative organisms but they have less activity against gram-positive organisms compared to the 1st generation cephalosporins.

Fourth generation cephalosporins

Cefepime expands the gram-negative coverage of the 3rd generation cephalosporins. It has similar coverage to that of the 3rd generation drug, ceftriaxone, which includes gram-negative and gram-positive organisms.

Fifth generation cephalosporins

The 5th generation cephalosporins, ceftaroline and ceftolozane, are noteworthy for their enhanced effects against methicillin-resistant Staphylococcus aureus and Pseudomonas.

See also Christopher Duplessis, MD, MPH and Nancy Crum-Cianflone, MD, MPH. Ceftaroline: A New Cephalosporin with Activity against Methicillin-Resistant Staphylococcus aureus (MRSA). Clin Med Rev Ther. 2011 Feb 10; 3: a2466. doi:10.4137/CMRT.S1637; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140339/. This is an article describing the cephalosporin ceftaroline including its coverage against multidrug-resistant strains of bacteria, mechanism of action, and pharmacokinetic and pharmacodynamics properties. Safety and efficacy studies are also discussed along with its low propensity for inducing resistance among bacteria.

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Cephalosporins are a class of β-lactam antibiotics derived from the fungus Cephalosporium.  This class of antibiotics works by inhibiting bacterial cell wall synthesis by binding to penicillin binding proteins, causing bacterial cell lysis.  Specific examples of penicillin binding proteins include carboxypeptidases and endopeptidases; these penicillin binding protein enzymes normally form the peptide cross links between peptidoglycans in bacterial cell walls.  However, in the presence of beta-lactam antibiotics, formation of these cross-links is disrupted, the cell wall becomes osmotically unstable, and bacteria burst from osmotic pressure.  Cephalosporins are both bactericidal and time dependent, meaning that they effectively kill susceptible bacteria as long as the plasma concentration of the antibiotic remains above the minimum inhibitory concentration between doses. 

The structures of the agents in this class vary greatly, but they generally share commonalities around a β-lactam ring (e.g. the “square” four membered ring).  In the figure, the functional group R2 determines both the anti-bacterial spectrum coverage and β-lactamase resistance, while R1 determines metabolism and pharmacokinetic parameters of the cephalosporin.

These drugs are renally eliminated and doses must be adjusted when renal dysfunction is present.  The most common adverse reactions to cephalosporins are gastrointestinal upset and an allergic reaction in the form of a rash.  Due to their structural similarities with penicillins, there is a slight chance individuals with penicillin allergies may experience cross-reactivity with cephalosporins.  What was once thought to be a 10% risk of cross-reactivity is now thought to be attributed to cross-contamination during manufacturing processes and is now believed to be closer to 1% with first generation cephalosporins and less likely with other generations.  The third and fourth generation cephalosporins have side chains that generally render them dissimilar enough to penicillins so as to not lead to cross-sensitivity; thus, individuals with a history of hives to penicillins can usually tolerate the newer cephalosporins without any problems.  However, to be on the safe side, in general, all cephalosporins are usually avoided in individuals that report a history of anaphylactic reactions to penicillins.

Resistance to cephalosporins arises via two different mechanisms.  Target-mediated resistance occurs when bacteria have alterations in penicillin binding proteins that reduce a cephalosporin’s affinity for binding to penicillin binding proteins.  Another mechanism of resistance occurs if the bacteria acquire β-lactamase enzymes, known as cephalosporinases, capable of lysing and opening the β-lactam ring, rendering the molecule inactive. 

There are various cephalosporins available on the market today.  They are commonly divided into different groups, called generations, based on the structure of their side chains, and thus their antimicrobial activities.

 

1st Generation Cephalosporins

First generation cephalosporins have good activity against gram-positive bacteria including penicillinase-producing streptococci and staphylococci and modest activity against gram-negative rods such as K. pneumonia, P. mirabilis, and E. coli.  However, they offer no reliable anaerobic coverage.   They, along with some penicillins, are often drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA).  Agents in this class include cephalexin, cefazolin, and cefadroxil.  Cephalexin is often used orally to treat skin infections and cellulitis. Cefazolin is commonly administered during surgery to prevent infections of the surgical site.    Chemically, cefazolin contains a N-methyl thiotetrazole (NMTT) functional group which has been linked to specific adverse effects.  Specifically, when alcohol is consumed, a disulfiram-like reaction characterized by unpleasant side effects like severe nausea and vomiting can occur when drugs with NMTT side chains are taken.  The NMTT chemical ring also interferes with vitamin K formation and can lead to an increased bleeding risk in some patients. 

 

2nd Generation Cephalosporins

Second generation agents include cefuroxime, cefoxitin, cefotetan, cefprozil, and cefaclor.  As a group, the second generation cephalosporins sacrifice some activity against gram-positive bacteria in favor of gaining more gram-negative coverage.  These drugs possess gram-negative coverage for H. influenza and M. catarrhalis, organisms that commonly cause upper respiratory tract infections as well as coverage for E. coli and other gram negative bacteria that cause uncomplicated urinary tract infections.  The drugs cefoxitin and cefotetan have added benefits of possessing anaerobic coverage for B. fragilis, a cause of intra-abdominal infections.  Cefotetan also has the NMTT functional group mentioned above with cefazolin and may produce a disulfiram-like reaction if alcohol is consumed; this side chain may also increase bleeding risk.  Cefaclor has been associated with a non-allergic rash caused by reactive intermediates that acetylate proteins and produce immunogenic complexes; however, this reaction is not a contraindication to use of other cephalosporins or penicillins.

 

3rd Generation Cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefixime, cefpodoxime, cefdinir, and ceftibuten are considered third generation cephalosporins.  Third generation cephalosporins cannot be used to treat staphylococcal or anaerobic infections, but do possess coverage against pneumococcal organisms.  Furthermore, third generation cephalosporins exhibit enhanced gram-negative activity and are useful for treating infections caused by Enterobacteriaceae, Serratia spp., and N. gonorrhea.  Ceftriaxone is often used to treat serious community-acquired pneumonia infections, but since it does not cover pseudomonas, it is not be an appropriate choice for health-care acquired pneumonia.   On the other hand, ceftazidime is a drug of choice for treating infections caused by P. aeruginosa including lung infections.  In the presence of central nervous system inflammation, ceftriaxone and cefotaxime can cross the blood brain barrier and can be used in combination with other drugs to treat meningitis.  Although most third generation drugs are eliminated predominantly by the kidneys, ceftriaxone has dual elimination with the kidneys and liver and can cause pseudocholelithiasis, which is a feeling like a person has a gall stone -- a situation that usually resolves after the medication is stopped.  In addition, ceftriaxone can precipitate in the gall bladder and lead to stone formation; in attempt to avoid this, the drug should never be administered with intravenous calcium.  Due to their relatively broad spectrum against normal gut bacterial flora, the agents in this generation are commonly implicated in causing C. difficile-associated diarrhea.

4th Generation Cephalosporin

Cefepime is considered to be a fourth generation cephalosporin.  It combines the gram-positive coverage of the first generation cephalosporins with the gram-negative coverage of the third generation cephalosporins.  Like ceftazidime of the third generation agents, cefepime lacks anaerobic coverage but is active against P. aeruginosa.  It is the broadest spectrum cephalosporin and is the drug of choice for Enterobacter spp.  Its use is often reserved for empiric treatment in hospitalized patients when coverage for gram-positive organisms, Enterobacteriaceae, or Pseudomonas spp is needed.

Rebecca Kramer, Kelly Karpa

Cephalosporins are a class of β-lactam antibiotics derived from the fungus Cephalosporium.  This class of antibiotics works by inhibiting bacterial cell wall synthesis by binding to penicillin binding proteins, causing bacterial cell lysis.  Specific examples of penicillin binding proteins include carboxypeptidases and endopeptidases; these penicillin binding protein enzymes normally form the peptide cross links between peptidoglycans in bacterial cell walls.  However, in the presence of beta-lactam antibiotics, formation of these cross-links is disrupted, the cell wall becomes osmotically unstable, and bacteria burst from osmotic pressure.  Cephalosporins are both bactericidal and time dependent, meaning that they effectively kill susceptible bacteria as long as the plasma concentration of the antibiotic remains above the minimum inhibitory concentration between doses. 

The structures of the agents in this class vary greatly, but they generally share commonalities around a β-lactam ring (e.g. the “square” four membered ring).  In the figure, the functional group R2 determines both the anti-bacterial spectrum coverage and β-lactamase resistance, while R1 determines metabolism and pharmacokinetic parameters of the cephalosporin.

These drugs are renally eliminated and doses must be adjusted when renal dysfunction is present.  The most common adverse reactions to cephalosporins are gastrointestinal upset and an allergic reaction in the form of a rash.  Due to their structural similarities with penicillins, there is a slight chance individuals with penicillin allergies may experience cross-reactivity with cephalosporins.  What was once thought to be a 10% risk of cross-reactivity is now thought to be attributed to cross-contamination during manufacturing processes and is now believed to be closer to 1% with first generation cephalosporins and less likely with other generations.  The third and fourth generation cephalosporins have side chains that generally render them dissimilar enough to penicillins so as to not lead to cross-sensitivity; thus, individuals with a history of hives to penicillins can usually tolerate the newer cephalosporins without any problems.  However, to be on the safe side, in general, all cephalosporins are usually avoided in individuals that report a history of anaphylactic reactions to penicillins.

Resistance to cephalosporins arises via two different mechanisms.  Target-mediated resistance occurs when bacteria have alterations in penicillin binding proteins that reduce a cephalosporin’s affinity for binding to penicillin binding proteins.  Another mechanism of resistance occurs if the bacteria acquire β-lactamase enzymes, known as cephalosporinases, capable of lysing and opening the β-lactam ring, rendering the molecule inactive. 

There are various cephalosporins available on the market today.  They are commonly divided into different groups, called generations, based on the structure of their side chains, and thus their antimicrobial activities.

 

1st Generation Cephalosporins

First generation cephalosporins have good activity against gram-positive bacteria including penicillinase-producing streptococci and staphylococci and modest activity against gram-negative rods such as K. pneumonia, P. mirabilis, and E. coli.  However, they offer no reliable anaerobic coverage.   They, along with some penicillins, are often drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA).  Agents in this class include cephalexin, cefazolin, and cefadroxil.  Cephalexin is often used orally to treat skin infections and cellulitis. Cefazolin is commonly administered during surgery to prevent infections of the surgical site.    Chemically, cefazolin contains a N-methyl thiotetrazole (NMTT) functional group which has been linked to specific adverse effects.  Specifically, when alcohol is consumed, a disulfiram-like reaction characterized by unpleasant side effects like severe nausea and vomiting can occur when drugs with NMTT side chains are taken.  The NMTT chemical ring also interferes with vitamin K formation and can lead to an increased bleeding risk in some patients. 

 

2nd Generation Cephalosporins

Second generation agents include cefuroxime, cefoxitin, cefotetan, cefprozil, and cefaclor.  As a group, the second generation cephalosporins sacrifice some activity against gram-positive bacteria in favor of gaining more gram-negative coverage.  These drugs possess gram-negative coverage for H. influenza and M. catarrhalis, organisms that commonly cause upper respiratory tract infections as well as coverage for E. coli and other gram negative bacteria that cause uncomplicated urinary tract infections.  The drugs cefoxitin and cefotetan have added benefits of possessing anaerobic coverage for B. fragilis, a cause of intra-abdominal infections.  Cefotetan also has the NMTT functional group mentioned above with cefazolin and may produce a disulfiram-like reaction if alcohol is consumed; this side chain may also increase bleeding risk.  Cefaclor has been associated with a non-allergic rash caused by reactive intermediates that acetylate proteins and produce immunogenic complexes; however, this reaction is not a contraindication to use of other cephalosporins or penicillins.

 

3rd Generation Cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefixime, cefpodoxime, cefdinir, and ceftibuten are considered third generation cephalosporins.  Third generation cephalosporins cannot be used to treat staphylococcal or anaerobic infections, but do possess coverage against pneumococcal organisms.  Furthermore, third generation cephalosporins exhibit enhanced gram-negative activity and are useful for treating infections caused by Enterobacteriaceae, Serratia spp., and N. gonorrhea.  Ceftriaxone is often used to treat serious community-acquired pneumonia infections, but since it does not cover pseudomonas, it is not be an appropriate choice for health-care acquired pneumonia.   On the other hand, ceftazidime is a drug of choice for treating infections caused by P. aeruginosa including lung infections.  In the presence of central nervous system inflammation, ceftriaxone and cefotaxime can cross the blood brain barrier and can be used in combination with other drugs to treat meningitis.  Although most third generation drugs are eliminated predominantly by the kidneys, ceftriaxone has dual elimination with the kidneys and liver and can cause pseudocholelithiasis, which is a feeling like a person has a gall stone -- a situation that usually resolves after the medication is stopped.  In addition, ceftriaxone can precipitate in the gall bladder and lead to stone formation; in attempt to avoid this, the drug should never be administered with intravenous calcium.  Due to their relatively broad spectrum against normal gut bacterial flora, the agents in this generation are commonly implicated in causing C. difficile-associated diarrhea.

4th Generation Cephalosporin

Cefepime is considered to be a fourth generation cephalosporin.  It combines the gram-positive coverage of the first generation cephalosporins with the gram-negative coverage of the third generation cephalosporins.  Like ceftazidime of the third generation agents, cefepime lacks anaerobic coverage but is active against P. aeruginosa.  It is the broadest spectrum cephalosporin and is the drug of choice for Enterobacter spp.  Its use is often reserved for empiric treatment in hospitalized patients when coverage for gram-positive organisms, Enterobacteriaceae, or Pseudomonas spp is needed.

Rebecca Kramer, Kelly Karpa

Cephalosporins are a class of β-lactam antibiotics derived from the fungus Cephalosporium.  This class of antibiotics works by inhibiting bacterial cell wall synthesis by binding to penicillin binding proteins, causing bacterial cell lysis.  Specific examples of penicillin binding proteins include carboxypeptidases and endopeptidases; these penicillin binding protein enzymes normally form the peptide cross links between peptidoglycans in bacterial cell walls.  However, in the presence of beta-lactam antibiotics, formation of these cross-links is disrupted, the cell wall becomes osmotically unstable, and bacteria burst from osmotic pressure.  Cephalosporins are both bactericidal and time dependent, meaning that they effectively kill susceptible bacteria as long as the plasma concentration of the antibiotic remains above the minimum inhibitory concentration between doses. 

The structures of the agents in this class vary greatly, but they generally share commonalities around a β-lactam ring (e.g. the “square” four membered ring).  In the figure, the functional group R2 determines both the anti-bacterial spectrum coverage and β-lactamase resistance, while R1 determines metabolism and pharmacokinetic parameters of the cephalosporin.

These drugs are renally eliminated and doses must be adjusted when renal dysfunction is present.  The most common adverse reactions to cephalosporins are gastrointestinal upset and an allergic reaction in the form of a rash.  Due to their structural similarities with penicillins, there is a slight chance individuals with penicillin allergies may experience cross-reactivity with cephalosporins.  What was once thought to be a 10% risk of cross-reactivity is now thought to be attributed to cross-contamination during manufacturing processes and is now believed to be closer to 1% with first generation cephalosporins and less likely with other generations.  The third and fourth generation cephalosporins have side chains that generally render them dissimilar enough to penicillins so as to not lead to cross-sensitivity; thus, individuals with a history of hives to penicillins can usually tolerate the newer cephalosporins without any problems.  However, to be on the safe side, in general, all cephalosporins are usually avoided in individuals that report a history of anaphylactic reactions to penicillins.

Resistance to cephalosporins arises via two different mechanisms.  Target-mediated resistance occurs when bacteria have alterations in penicillin binding proteins that reduce a cephalosporin’s affinity for binding to penicillin binding proteins.  Another mechanism of resistance occurs if the bacteria acquire β-lactamase enzymes, known as cephalosporinases, capable of lysing and opening the β-lactam ring, rendering the molecule inactive. 

There are various cephalosporins available on the market today.  They are commonly divided into different groups, called generations, based on the structure of their side chains, and thus their antimicrobial activities.

 

1st Generation Cephalosporins

First generation cephalosporins have good activity against gram-positive bacteria including penicillinase-producing streptococci and staphylococci and modest activity against gram-negative rods such as K. pneumonia, P. mirabilis, and E. coli.  However, they offer no reliable anaerobic coverage.   They, along with some penicillins, are often drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA).  Agents in this class include cephalexin, cefazolin, and cefadroxil.  Cephalexin is often used orally to treat skin infections and cellulitis. Cefazolin is commonly administered during surgery to prevent infections of the surgical site.    Chemically, cefazolin contains a N-methyl thiotetrazole (NMTT) functional group which has been linked to specific adverse effects.  Specifically, when alcohol is consumed, a disulfiram-like reaction characterized by unpleasant side effects like severe nausea and vomiting can occur when drugs with NMTT side chains are taken.  The NMTT chemical ring also interferes with vitamin K formation and can lead to an increased bleeding risk in some patients. 

 

2nd Generation Cephalosporins

Second generation agents include cefuroxime, cefoxitin, cefotetan, cefprozil, and cefaclor.  As a group, the second generation cephalosporins sacrifice some activity against gram-positive bacteria in favor of gaining more gram-negative coverage.  These drugs possess gram-negative coverage for H. influenza and M. catarrhalis, organisms that commonly cause upper respiratory tract infections as well as coverage for E. coli and other gram negative bacteria that cause uncomplicated urinary tract infections.  The drugs cefoxitin and cefotetan have added benefits of possessing anaerobic coverage for B. fragilis, a cause of intra-abdominal infections.  Cefotetan also has the NMTT functional group mentioned above with cefazolin and may produce a disulfiram-like reaction if alcohol is consumed; this side chain may also increase bleeding risk.  Cefaclor has been associated with a non-allergic rash caused by reactive intermediates that acetylate proteins and produce immunogenic complexes; however, this reaction is not a contraindication to use of other cephalosporins or penicillins.

 

3rd Generation Cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefixime, cefpodoxime, cefdinir, and ceftibuten are considered third generation cephalosporins.  Third generation cephalosporins cannot be used to treat staphylococcal or anaerobic infections, but do possess coverage against pneumococcal organisms.  Furthermore, third generation cephalosporins exhibit enhanced gram-negative activity and are useful for treating infections caused by Enterobacteriaceae, Serratia spp., and N. gonorrhea.  Ceftriaxone is often used to treat serious community-acquired pneumonia infections, but since it does not cover pseudomonas, it is not be an appropriate choice for health-care acquired pneumonia.   On the other hand, ceftazidime is a drug of choice for treating infections caused by P. aeruginosa including lung infections.  In the presence of central nervous system inflammation, ceftriaxone and cefotaxime can cross the blood brain barrier and can be used in combination with other drugs to treat meningitis.  Although most third generation drugs are eliminated predominantly by the kidneys, ceftriaxone has dual elimination with the kidneys and liver and can cause pseudocholelithiasis, which is a feeling like a person has a gall stone -- a situation that usually resolves after the medication is stopped.  In addition, ceftriaxone can precipitate in the gall bladder and lead to stone formation; in attempt to avoid this, the drug should never be administered with intravenous calcium.  Due to their relatively broad spectrum against normal gut bacterial flora, the agents in this generation are commonly implicated in causing C. difficile-associated diarrhea.

4th Generation Cephalosporin

Cefepime is considered to be a fourth generation cephalosporin.  It combines the gram-positive coverage of the first generation cephalosporins with the gram-negative coverage of the third generation cephalosporins.  Like ceftazidime of the third generation agents, cefepime lacks anaerobic coverage but is active against P. aeruginosa.  It is the broadest spectrum cephalosporin and is the drug of choice for Enterobacter spp.  Its use is often reserved for empiric treatment in hospitalized patients when coverage for gram-positive organisms, Enterobacteriaceae, or Pseudomonas spp is needed.

Rebecca Kramer, Kelly Karpa

Cephalosporins are a class of β-lactam antibiotics derived from the fungus Cephalosporium.  This class of antibiotics works by inhibiting bacterial cell wall synthesis by binding to penicillin binding proteins, causing bacterial cell lysis.  Specific examples of penicillin binding proteins include carboxypeptidases and endopeptidases; these penicillin binding protein enzymes normally form the peptide cross links between peptidoglycans in bacterial cell walls.  However, in the presence of beta-lactam antibiotics, formation of these cross-links is disrupted, the cell wall becomes osmotically unstable, and bacteria burst from osmotic pressure.  Cephalosporins are both bactericidal and time dependent, meaning that they effectively kill susceptible bacteria as long as the plasma concentration of the antibiotic remains above the minimum inhibitory concentration between doses. 

The structures of the agents in this class vary greatly, but they generally share commonalities around a β-lactam ring (e.g. the “square” four membered ring).  In the figure, the functional group R2 determines both the anti-bacterial spectrum coverage and β-lactamase resistance, while R1 determines metabolism and pharmacokinetic parameters of the cephalosporin.

These drugs are renally eliminated and doses must be adjusted when renal dysfunction is present.  The most common adverse reactions to cephalosporins are gastrointestinal upset and an allergic reaction in the form of a rash.  Due to their structural similarities with penicillins, there is a slight chance individuals with penicillin allergies may experience cross-reactivity with cephalosporins.  What was once thought to be a 10% risk of cross-reactivity is now thought to be attributed to cross-contamination during manufacturing processes and is now believed to be closer to 1% with first generation cephalosporins and less likely with other generations.  The third and fourth generation cephalosporins have side chains that generally render them dissimilar enough to penicillins so as to not lead to cross-sensitivity; thus, individuals with a history of hives to penicillins can usually tolerate the newer cephalosporins without any problems.  However, to be on the safe side, in general, all cephalosporins are usually avoided in individuals that report a history of anaphylactic reactions to penicillins.

Resistance to cephalosporins arises via two different mechanisms.  Target-mediated resistance occurs when bacteria have alterations in penicillin binding proteins that reduce a cephalosporin’s affinity for binding to penicillin binding proteins.  Another mechanism of resistance occurs if the bacteria acquire β-lactamase enzymes, known as cephalosporinases, capable of lysing and opening the β-lactam ring, rendering the molecule inactive. 

There are various cephalosporins available on the market today.  They are commonly divided into different groups, called generations, based on the structure of their side chains, and thus their antimicrobial activities.

 

1st Generation Cephalosporins

First generation cephalosporins have good activity against gram-positive bacteria including penicillinase-producing streptococci and staphylococci and modest activity against gram-negative rods such as K. pneumonia, P. mirabilis, and E. coli.  However, they offer no reliable anaerobic coverage.   They, along with some penicillins, are often drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA).  Agents in this class include cephalexin, cefazolin, and cefadroxil.  Cephalexin is often used orally to treat skin infections and cellulitis. Cefazolin is commonly administered during surgery to prevent infections of the surgical site.    Chemically, cefazolin contains a N-methyl thiotetrazole (NMTT) functional group which has been linked to specific adverse effects.  Specifically, when alcohol is consumed, a disulfiram-like reaction characterized by unpleasant side effects like severe nausea and vomiting can occur when drugs with NMTT side chains are taken.  The NMTT chemical ring also interferes with vitamin K formation and can lead to an increased bleeding risk in some patients. 

 

2nd Generation Cephalosporins

Second generation agents include cefuroxime, cefoxitin, cefotetan, cefprozil, and cefaclor.  As a group, the second generation cephalosporins sacrifice some activity against gram-positive bacteria in favor of gaining more gram-negative coverage.  These drugs possess gram-negative coverage for H. influenza and M. catarrhalis, organisms that commonly cause upper respiratory tract infections as well as coverage for E. coli and other gram negative bacteria that cause uncomplicated urinary tract infections.  The drugs cefoxitin and cefotetan have added benefits of possessing anaerobic coverage for B. fragilis, a cause of intra-abdominal infections.  Cefotetan also has the NMTT functional group mentioned above with cefazolin and may produce a disulfiram-like reaction if alcohol is consumed; this side chain may also increase bleeding risk.  Cefaclor has been associated with a non-allergic rash caused by reactive intermediates that acetylate proteins and produce immunogenic complexes; however, this reaction is not a contraindication to use of other cephalosporins or penicillins.

 

3rd Generation Cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefixime, cefpodoxime, cefdinir, and ceftibuten are considered third generation cephalosporins.  Third generation cephalosporins cannot be used to treat staphylococcal or anaerobic infections, but do possess coverage against pneumococcal organisms.  Furthermore, third generation cephalosporins exhibit enhanced gram-negative activity and are useful for treating infections caused by Enterobacteriaceae, Serratia spp., and N. gonorrhea.  Ceftriaxone is often used to treat serious community-acquired pneumonia infections, but since it does not cover pseudomonas, it is not be an appropriate choice for health-care acquired pneumonia.   On the other hand, ceftazidime is a drug of choice for treating infections caused by P. aeruginosa including lung infections.  In the presence of central nervous system inflammation, ceftriaxone and cefotaxime can cross the blood brain barrier and can be used in combination with other drugs to treat meningitis.  Although most third generation drugs are eliminated predominantly by the kidneys, ceftriaxone has dual elimination with the kidneys and liver and can cause pseudocholelithiasis, which is a feeling like a person has a gall stone -- a situation that usually resolves after the medication is stopped.  In addition, ceftriaxone can precipitate in the gall bladder and lead to stone formation; in attempt to avoid this, the drug should never be administered with intravenous calcium.  Due to their relatively broad spectrum against normal gut bacterial flora, the agents in this generation are commonly implicated in causing C. difficile-associated diarrhea.

4th Generation Cephalosporin

Cefepime is considered to be a fourth generation cephalosporin.  It combines the gram-positive coverage of the first generation cephalosporins with the gram-negative coverage of the third generation cephalosporins.  Like ceftazidime of the third generation agents, cefepime lacks anaerobic coverage but is active against P. aeruginosa.  It is the broadest spectrum cephalosporin and is the drug of choice for Enterobacter spp.  Its use is often reserved for empiric treatment in hospitalized patients when coverage for gram-positive organisms, Enterobacteriaceae, or Pseudomonas spp is needed.

Rebecca Kramer, Kelly Karpa

Macrolides

Macrolides consist of a large lactone ring with several deoxy sugars. Erythromycin and clarithromycin are representative examples. These drugs bind to the 50S subunit, near the peptidyltransferase centre (PTC). Therefore, the growing peptide cannot “lean over” and is kept in the A site. The subsequent events, i.e. the shifting of the “uncharged” tRNA to E site and ribosomal sliding movement, will not occur. GI disturbances and rash are common. There are rare occurrences of cholestatic hepatitis. Erythromycin is also a P450 inhibitor. One use of erythromycin is against S. pneumoniae if there is penicillin allergy. Common mechanisms of resistance to macrolides include decreased drug permeability, active drug efflux and most important of all, ribosomal alteration. The 50S ribosomal subunit is methylated, and this affects not only macrolide binding but also that of lincosamides (i.e. clindamycin) and streptogramins. This type of resistance is therefore referred to as MLS B-type resistance. The MLS B-type resistance is widespread across many bacterial species.

Telithromycin is a ketolide based on macrolides, but with a ketone and carbamate group. The ketone group decreases its susceptibility to MLS B-type resistance and active drug efflux while the carbamate group increases binding strength to ribosome. Antibacterial spectrum of telithromycin is similar to macrolides, but with better potency. However, potentially fatal hepatoxicity has limited its use.

Links to PubChem entries: azithromycin, clarithromycin, telithromycin. These entries provide the key physico-chemical and pharmacological properties of the drugs. Synopses of individual reports on adverse drug reactions and examples of available drug formulations are also provided.

Dr Willmann Liang

Azithromycin, clarithromycin, telithromycin

This article provides an overview of the general pharmacology of macrolides.  Important unwanted effects are described in great detail.  With respect to resistance mechanisms, the more susceptible typical macrolides (e.g. azithromycin and clarithromycin) are compared with the more superior telithromycin.

Advanced level

Author: Amy L Graziani

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Macrolides consist of a large lactone ring with several deoxy sugars. Erythromycin and clarithromycin are representative examples. These drugs bind to the 50S subunit, near the peptidyltransferase centre (PTC). Therefore, the growing peptide cannot “lean over” and is kept in the A site. The subsequent events, i.e. the shifting of the “uncharged” tRNA to E site and ribosomal sliding movement, will not occur. GI disturbances and rash are common. There are rare occurrences of cholestatic hepatitis. Erythromycin is also a P450 inhibitor. One use of erythromycin is against S. pneumoniae if there is penicillin allergy. Common mechanisms of resistance to macrolides include decreased drug permeability, active drug efflux and most important of all, ribosomal alteration. The 50S ribosomal subunit is methylated, and this affects not only macrolide binding but also that of lincosamides (i.e. clindamycin) and streptogramins. This type of resistance is therefore referred to as MLS B-type resistance. The MLS B-type resistance is widespread across many bacterial species.

Telithromycin is a ketolide based on macrolides, but with a ketone and carbamate group. The ketone group decreases its susceptibility to MLS B-type resistance and active drug efflux while the carbamate group increases binding strength to ribosome. Antibacterial spectrum of telithromycin is similar to macrolides, but with better potency. However, potentially fatal hepatoxicity has limited its use.

Links to PubChem entries: azithromycin, clarithromycin, telithromycin. These entries provide the key physico-chemical and pharmacological properties of the drugs. Synopses of individual reports on adverse drug reactions and examples of available drug formulations are also provided.

Dr Willmann Liang

Classes of antibiotics that target bacterial ribosome: macrolides

This narrated video gives an overview of the mechanisms of action of antibiotics that act at the bacterial ribosomes, thus inhibiting bacterial protein synthesis.  Macrolides are introduced at 3:36 of the video.  Mechanisms of drug resistance are also briefly introduced, the erm gene being notable example of the MLS B-type resistance.

Intermediate level 

Author: MedLecturesMadeEasy

No votes yet

Macrolides consist of a large lactone ring with several deoxy sugars. Erythromycin and clarithromycin are representative examples. These drugs bind to the 50S subunit, near the peptidyltransferase centre (PTC). Therefore, the growing peptide cannot “lean over” and is kept in the A site. The subsequent events, i.e. the shifting of the “uncharged” tRNA to E site and ribosomal sliding movement, will not occur. GI disturbances and rash are common. There are rare occurrences of cholestatic hepatitis. Erythromycin is also a P450 inhibitor. One use of erythromycin is against S. pneumoniae if there is penicillin allergy. Common mechanisms of resistance to macrolides include decreased drug permeability, active drug efflux and most important of all, ribosomal alteration. The 50S ribosomal subunit is methylated, and this affects not only macrolide binding but also that of lincosamides (i.e. clindamycin) and streptogramins. This type of resistance is therefore referred to as MLS B-type resistance. The MLS B-type resistance is widespread across many bacterial species.

Telithromycin is a ketolide based on macrolides, but with a ketone and carbamate group. The ketone group decreases its susceptibility to MLS B-type resistance and active drug efflux while the carbamate group increases binding strength to ribosome. Antibacterial spectrum of telithromycin is similar to macrolides, but with better potency. However, potentially fatal hepatoxicity has limited its use.

Links to PubChem entries: azithromycin, clarithromycin, telithromycin. These entries provide the key physico-chemical and pharmacological properties of the drugs. Synopses of individual reports on adverse drug reactions and examples of available drug formulations are also provided.

Dr Willmann Liang

Macrolides: Mechanisms of action and resistance

The first part of this narrated video describes the mechanisms of action of macrolides.  From 3:05 onward, mechanisms of resistance to macrolides are introduced.  Specific reference is made to the erm gene, efflux pumps.

Advanced level.

Author: Mechanisms in Medicine

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Penicillins and other β-lactam antibiotics

β-lactam antibiotics are so-called because they all contain a β-lactam ring in their chemical structures. In general these antibiotics act to inhibit bacterial wall synthesis. They are broad-spectrum antibiotics with activity against both Gram +ve and Gram -ve bacterial strains.

Subgroups include: penicillin derivatives (penams) which are discussed in more detail below, cephalosporins (cephems), monobactams, carbapenems, and carbacephems (which are reviewed more extensively in other topics within this Drugs for Infections module.

Bacteria can produce β-lactamase as a mechanism of acquired resistance to β-lactam antibiotics. Co-administration of β-lactamase inhibitors can partially mitigate resistance.

β-lactamase-sensitive penicillins

Ampicillin is inactivated by penicillinases. Since the majority of staphylococci and E. coli strains and some Haemophilus influenzae strains are now resistant to ampicillin, it should not be used in the hospital setting or without first considering the likelihood of resistance. The main indications for ampicillin treatment are exacerbations of chronic bronchitis and middle ear infections due to Streptococcus pneumoniae and H. influenzae, and for urinary-tract infections.

A fixed-dose combination of ampicillin plus flucloxacillin (co-fluampicil) is available to treat streptococci or staphylococci infections such as cellulitis.

Amoxicillin, a derivative of ampicillin with improved oral absorption, has a similar antibacterial spectrum. It is notably used for the treatment of Lyme disease.

Co-amoxiclav (amoxicillin + clavulanic acid) is active against β-lactamase-producing bacteria that are resistant to amoxicillin, such as resistant strains of Staph. aureus, E. coli, and H. influenzae, as well as many Bacteroides and Klebsiella spp. Its use should be restricted to the treatment of infections likely, or known, to be caused by amoxicillin-resistant β-lactamase producing bacterial strains.

Benzylpenicillin (Penicillin G) is inactivated by gastric acid so has to be delivered by injection. It is effective against many streptococcal (including pneumococcal), gonococcal, and meningococcal infections, anthrax, diphtheria, gas-gangrene, and leptospirosis. Some pneumococci, meningococci, and gonococci strains are less sensitive to benzylpenicillin. Although benzylpenicillin is active against tetanus, treatment with metronidazole is the preferred option.

Benzathine benzylpenicillin is given by intramuscular injection to treat early syphilis and late latent syphilis.

Phenoxymethylpenicillin (Penicillin V) is similarly active to benzylpenicillin but is acid-resistant, so can be delivered orally. The principal indications for its use are respiratory-tract infections in children, streptococcal tonsillitis, and for continuing benzylpenicillin-initiated treatment when clinical response has begun. Phenoxymethylpenicillin should not be used for meningococcal or gonococcal infections.

Penicillinase- and β-lactamase-resistant penicillins

Flucloxacillin is not inactivated by penicillinases so it is effective against infections caused by penicillin-resistant staphylococci, and this is its principal use. It is acid-resistant and orally active.

Temocillin is stable against a wide range of β-lactamases. Its use should be reserved for the treatment of infections caused by β-lactamase-producing strains of Gram -ve bacteria, including those that are resistant to third-generation cephalosporins. Temocillin is not active against Pseudomonas aeruginosa or Acinetobacter spp.

Antipseudomonal penicillins

Piperacillin (a ureidopenicillin) is only available in a fixed-dose combination with the β-lactamase inhibitor tazobactam.

Ticarcillin (a carboxypenicillin) is only available in a fixed-dose combination with β-lactamase inhibiting clavulanic acid.

Both of these preparations are broad spectrum antibiotics that are effective against a range of Gram +ve , Gram -ve bacteria, and anaerobic bacteria. Piperacillin + tazobactam is active against a wider range of Gram -ve organisms than ticarcillin + clavulanic acid and it is more active against Pseudomonas aeruginosa. Neither of these antibacterials combat MRSA. They are typically used to treat septicaemia, hospital-acquired pneumonia, and complicated infections involving the urinary tract, skin and soft tissues, or intra-abdomen. Co-administration of an aminoglycoside (e.g. gentamicin) with these antipseudomonal penicillin preparations effectively combats severe pseudomonas infections.

Beta lactamase inhibitors

This is a short animated guide to β-lactamase inhibitors that was produced by Ryan Sheehy. It is suitable for beginners.

No votes yet

β-lactam antibiotics are so-called because they all contain a β-lactam ring in their chemical structures. In general these antibiotics act to inhibit bacterial wall synthesis. They are broad-spectrum antibiotics with activity against both Gram +ve and Gram -ve bacterial strains.

Subgroups include: penicillin derivatives (penams) which are discussed in more detail below, cephalosporins (cephems), monobactams, carbapenems, and carbacephems (which are reviewed more extensively in other topics within this Drugs for Infections module.

Bacteria can produce β-lactamase as a mechanism of acquired resistance to β-lactam antibiotics. Co-administration of β-lactamase inhibitors can partially mitigate resistance.

β-lactamase-sensitive penicillins

Ampicillin is inactivated by penicillinases. Since the majority of staphylococci and E. coli strains and some Haemophilus influenzae strains are now resistant to ampicillin, it should not be used in the hospital setting or without first considering the likelihood of resistance. The main indications for ampicillin treatment are exacerbations of chronic bronchitis and middle ear infections due to Streptococcus pneumoniae and H. influenzae, and for urinary-tract infections.

A fixed-dose combination of ampicillin plus flucloxacillin (co-fluampicil) is available to treat streptococci or staphylococci infections such as cellulitis.

Amoxicillin, a derivative of ampicillin with improved oral absorption, has a similar antibacterial spectrum. It is notably used for the treatment of Lyme disease.

Co-amoxiclav (amoxicillin + clavulanic acid) is active against β-lactamase-producing bacteria that are resistant to amoxicillin, such as resistant strains of Staph. aureus, E. coli, and H. influenzae, as well as many Bacteroides and Klebsiella spp. Its use should be restricted to the treatment of infections likely, or known, to be caused by amoxicillin-resistant β-lactamase producing bacterial strains.

Benzylpenicillin (Penicillin G) is inactivated by gastric acid so has to be delivered by injection. It is effective against many streptococcal (including pneumococcal), gonococcal, and meningococcal infections, anthrax, diphtheria, gas-gangrene, and leptospirosis. Some pneumococci, meningococci, and gonococci strains are less sensitive to benzylpenicillin. Although benzylpenicillin is active against tetanus, treatment with metronidazole is the preferred option.

Benzathine benzylpenicillin is given by intramuscular injection to treat early syphilis and late latent syphilis.

Phenoxymethylpenicillin (Penicillin V) is similarly active to benzylpenicillin but is acid-resistant, so can be delivered orally. The principal indications for its use are respiratory-tract infections in children, streptococcal tonsillitis, and for continuing benzylpenicillin-initiated treatment when clinical response has begun. Phenoxymethylpenicillin should not be used for meningococcal or gonococcal infections.

Penicillinase- and β-lactamase-resistant penicillins

Flucloxacillin is not inactivated by penicillinases so it is effective against infections caused by penicillin-resistant staphylococci, and this is its principal use. It is acid-resistant and orally active.

Temocillin is stable against a wide range of β-lactamases. Its use should be reserved for the treatment of infections caused by β-lactamase-producing strains of Gram -ve bacteria, including those that are resistant to third-generation cephalosporins. Temocillin is not active against Pseudomonas aeruginosa or Acinetobacter spp.

Antipseudomonal penicillins

Piperacillin (a ureidopenicillin) is only available in a fixed-dose combination with the β-lactamase inhibitor tazobactam.

Ticarcillin (a carboxypenicillin) is only available in a fixed-dose combination with β-lactamase inhibiting clavulanic acid.

Both of these preparations are broad spectrum antibiotics that are effective against a range of Gram +ve , Gram -ve bacteria, and anaerobic bacteria. Piperacillin + tazobactam is active against a wider range of Gram -ve organisms than ticarcillin + clavulanic acid and it is more active against Pseudomonas aeruginosa. Neither of these antibacterials combat MRSA. They are typically used to treat septicaemia, hospital-acquired pneumonia, and complicated infections involving the urinary tract, skin and soft tissues, or intra-abdomen. Co-administration of an aminoglycoside (e.g. gentamicin) with these antipseudomonal penicillin preparations effectively combats severe pseudomonas infections.

Penicillinase resistant penicillins

This is a short animated video that describes Penicillinase resistant penicillins that was produced by Ryan Sheehy. It is suitable for beginners.

No votes yet

β-lactam antibiotics are so-called because they all contain a β-lactam ring in their chemical structures. In general these antibiotics act to inhibit bacterial wall synthesis. They are broad-spectrum antibiotics with activity against both Gram +ve and Gram -ve bacterial strains.

Subgroups include: penicillin derivatives (penams) which are discussed in more detail below, cephalosporins (cephems), monobactams, carbapenems, and carbacephems (which are reviewed more extensively in other topics within this Drugs for Infections module.

Bacteria can produce β-lactamase as a mechanism of acquired resistance to β-lactam antibiotics. Co-administration of β-lactamase inhibitors can partially mitigate resistance.

β-lactamase-sensitive penicillins

Ampicillin is inactivated by penicillinases. Since the majority of staphylococci and E. coli strains and some Haemophilus influenzae strains are now resistant to ampicillin, it should not be used in the hospital setting or without first considering the likelihood of resistance. The main indications for ampicillin treatment are exacerbations of chronic bronchitis and middle ear infections due to Streptococcus pneumoniae and H. influenzae, and for urinary-tract infections.

A fixed-dose combination of ampicillin plus flucloxacillin (co-fluampicil) is available to treat streptococci or staphylococci infections such as cellulitis.

Amoxicillin, a derivative of ampicillin with improved oral absorption, has a similar antibacterial spectrum. It is notably used for the treatment of Lyme disease.

Co-amoxiclav (amoxicillin + clavulanic acid) is active against β-lactamase-producing bacteria that are resistant to amoxicillin, such as resistant strains of Staph. aureus, E. coli, and H. influenzae, as well as many Bacteroides and Klebsiella spp. Its use should be restricted to the treatment of infections likely, or known, to be caused by amoxicillin-resistant β-lactamase producing bacterial strains.

Benzylpenicillin (Penicillin G) is inactivated by gastric acid so has to be delivered by injection. It is effective against many streptococcal (including pneumococcal), gonococcal, and meningococcal infections, anthrax, diphtheria, gas-gangrene, and leptospirosis. Some pneumococci, meningococci, and gonococci strains are less sensitive to benzylpenicillin. Although benzylpenicillin is active against tetanus, treatment with metronidazole is the preferred option.

Benzathine benzylpenicillin is given by intramuscular injection to treat early syphilis and late latent syphilis.

Phenoxymethylpenicillin (Penicillin V) is similarly active to benzylpenicillin but is acid-resistant, so can be delivered orally. The principal indications for its use are respiratory-tract infections in children, streptococcal tonsillitis, and for continuing benzylpenicillin-initiated treatment when clinical response has begun. Phenoxymethylpenicillin should not be used for meningococcal or gonococcal infections.

Penicillinase- and β-lactamase-resistant penicillins

Flucloxacillin is not inactivated by penicillinases so it is effective against infections caused by penicillin-resistant staphylococci, and this is its principal use. It is acid-resistant and orally active.

Temocillin is stable against a wide range of β-lactamases. Its use should be reserved for the treatment of infections caused by β-lactamase-producing strains of Gram -ve bacteria, including those that are resistant to third-generation cephalosporins. Temocillin is not active against Pseudomonas aeruginosa or Acinetobacter spp.

Antipseudomonal penicillins

Piperacillin (a ureidopenicillin) is only available in a fixed-dose combination with the β-lactamase inhibitor tazobactam.

Ticarcillin (a carboxypenicillin) is only available in a fixed-dose combination with β-lactamase inhibiting clavulanic acid.

Both of these preparations are broad spectrum antibiotics that are effective against a range of Gram +ve , Gram -ve bacteria, and anaerobic bacteria. Piperacillin + tazobactam is active against a wider range of Gram -ve organisms than ticarcillin + clavulanic acid and it is more active against Pseudomonas aeruginosa. Neither of these antibacterials combat MRSA. They are typically used to treat septicaemia, hospital-acquired pneumonia, and complicated infections involving the urinary tract, skin and soft tissues, or intra-abdomen. Co-administration of an aminoglycoside (e.g. gentamicin) with these antipseudomonal penicillin preparations effectively combats severe pseudomonas infections.

Penicillins

This short video (4:32) is part of an introductory series of videos on antibiotic classes produced by Ryan Sheehy of Kansas City University. It uses a narrated animation to introduce you to the basic structure and mechanisms of action of penicillins, and mechanisms of antimicrobial resistance to penicillins. Penicillins are beta-lactam antibiotics which interfere with the synthesis of the bacterial cell wall peptidoglycan. They do this by inhibiting penicillin binding proteins, transpeptidase enzymes  that normally crosslink the peptide chains attached to the backbone of the peptidoglycan. Inhibition of this crosslinking by penicillins leads to a lack of cell wall rigidity and bacterial cell death. Bacteria can produce β-lactamase as a mechanism of acquired resistance to β-lactam antibiotics. Other mechanisms of resistance such as alterations of porins are discussed. Videos that follow discuss specific penicillin drug classes.

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β-lactam antibiotics are so-called because they all contain a β-lactam ring in their chemical structures. In general these antibiotics act to inhibit bacterial wall synthesis. They are broad-spectrum antibiotics with activity against both Gram +ve and Gram -ve bacterial strains.

Subgroups include: penicillin derivatives (penams) which are discussed in more detail below, cephalosporins (cephems), monobactams, carbapenems, and carbacephems (which are reviewed more extensively in other topics within this Drugs for Infections module.

Bacteria can produce β-lactamase as a mechanism of acquired resistance to β-lactam antibiotics. Co-administration of β-lactamase inhibitors can partially mitigate resistance.

β-lactamase-sensitive penicillins

Ampicillin is inactivated by penicillinases. Since the majority of staphylococci and E. coli strains and some Haemophilus influenzae strains are now resistant to ampicillin, it should not be used in the hospital setting or without first considering the likelihood of resistance. The main indications for ampicillin treatment are exacerbations of chronic bronchitis and middle ear infections due to Streptococcus pneumoniae and H. influenzae, and for urinary-tract infections.

A fixed-dose combination of ampicillin plus flucloxacillin (co-fluampicil) is available to treat streptococci or staphylococci infections such as cellulitis.

Amoxicillin, a derivative of ampicillin with improved oral absorption, has a similar antibacterial spectrum. It is notably used for the treatment of Lyme disease.

Co-amoxiclav (amoxicillin + clavulanic acid) is active against β-lactamase-producing bacteria that are resistant to amoxicillin, such as resistant strains of Staph. aureus, E. coli, and H. influenzae, as well as many Bacteroides and Klebsiella spp. Its use should be restricted to the treatment of infections likely, or known, to be caused by amoxicillin-resistant β-lactamase producing bacterial strains.

Benzylpenicillin (Penicillin G) is inactivated by gastric acid so has to be delivered by injection. It is effective against many streptococcal (including pneumococcal), gonococcal, and meningococcal infections, anthrax, diphtheria, gas-gangrene, and leptospirosis. Some pneumococci, meningococci, and gonococci strains are less sensitive to benzylpenicillin. Although benzylpenicillin is active against tetanus, treatment with metronidazole is the preferred option.

Benzathine benzylpenicillin is given by intramuscular injection to treat early syphilis and late latent syphilis.

Phenoxymethylpenicillin (Penicillin V) is similarly active to benzylpenicillin but is acid-resistant, so can be delivered orally. The principal indications for its use are respiratory-tract infections in children, streptococcal tonsillitis, and for continuing benzylpenicillin-initiated treatment when clinical response has begun. Phenoxymethylpenicillin should not be used for meningococcal or gonococcal infections.

Penicillinase- and β-lactamase-resistant penicillins

Flucloxacillin is not inactivated by penicillinases so it is effective against infections caused by penicillin-resistant staphylococci, and this is its principal use. It is acid-resistant and orally active.

Temocillin is stable against a wide range of β-lactamases. Its use should be reserved for the treatment of infections caused by β-lactamase-producing strains of Gram -ve bacteria, including those that are resistant to third-generation cephalosporins. Temocillin is not active against Pseudomonas aeruginosa or Acinetobacter spp.

Antipseudomonal penicillins

Piperacillin (a ureidopenicillin) is only available in a fixed-dose combination with the β-lactamase inhibitor tazobactam.

Ticarcillin (a carboxypenicillin) is only available in a fixed-dose combination with β-lactamase inhibiting clavulanic acid.

Both of these preparations are broad spectrum antibiotics that are effective against a range of Gram +ve , Gram -ve bacteria, and anaerobic bacteria. Piperacillin + tazobactam is active against a wider range of Gram -ve organisms than ticarcillin + clavulanic acid and it is more active against Pseudomonas aeruginosa. Neither of these antibacterials combat MRSA. They are typically used to treat septicaemia, hospital-acquired pneumonia, and complicated infections involving the urinary tract, skin and soft tissues, or intra-abdomen. Co-administration of an aminoglycoside (e.g. gentamicin) with these antipseudomonal penicillin preparations effectively combats severe pseudomonas infections.

Penicillin G

This short video (3:22) is part of an introductory series of videos on antibiotic classes produced by Ryan Sheehy of Kansas City University. It uses a narrated animation to introduce you to the basic structure, mechanisms of action and adverse effects of penicillin G (benzylpenicillin). Penicillin G is the original penicillin that was discovered in 1928 and first used in humans in the 1940s. It is active against a wide range of microorganisms, however its use is hindered by susceptibility to β-lactamases. Penicillin G has greatest activity against Gram-positive bacteria (e.g. Streptococcus pneumoniae, Streptococcus pyogenes), some Gram-negative cocci (e.g. Neisseria meningitidis, Neisseria gonorrhoeae) and non-β-lactamase producing anaerobes. Adverse effects include hypersensitivity (penicillin allergy) and gastrointestinal disturbances.

Average: 2.7 (9 votes)

Quinolones

Bacteria replicate DNA via a unique enzyme called DNA gyrase (or topoisomerase II). DNA at the replication fork exist in a positively-supercoiled arrangement and the structure is strained. DNA gyrase nicks one strand of the DNA (say at a supercoiled segment behind) and reseals the strand after it un-coils at the front. This process restores the usual, negatively-supercoiled and stabilised, unstrained state. Another enzyme, topoisomerase IV, acts to untangle the newly replicated DNA. Both topoisomerases II & IV can be inhibited by fluoroquinolones, but activity against topoisomerase II is more clinically relevant at present.

Ciprofloxacin is a representative example of fluoroquinolones, so named because compounds in the class possess a fluorine. Fluoroquinolones inhibit the activity of DNA gyrase, thus stopping DNA replication. Drugs in this class should be avoided in pregnant women (concerning fetus) and those under age 18 as the developing bones and cartilage will be affected. Unwanted effects are infrequent and mild, but ciprofloxacin is a known cytochrome P450 inhibitor. Thus, interactions with other P450 inhibitors such as theophylline can produce CNS effects such as headache, dizziness and convulsions.

Fluoroquinolones have a broad spectrum of antibacterial activity, but usage is best reserved for Gram-negative (Gm-) bacteria, including against Acinetobacter baumannii & Pseudomonas aeruginosa (combined with aminoglycoside), Haemophilus influenzae, enterobacteria (Enterobacter, E. coli, K. pneumoniae). Resistance to fluoroquinolones may arise most commonly when the structure of DNA gyrase is altered. This may result in weaker drug-binding or a binding site that is shielded from the drug. It should also be noted that inactivation by acetylation occurs via an enzyme that does the same to aminoglycosides.

Links to PubChem entries: ciprofloxacin (a second-generation fluoroquinolone); levoflaxacin (a third-generation fluoroquinolone); moxifloxacin (a fourth-generation fluoroquinolone). These entries list the key physico-chemical and pharmacological properties of these fluoroquinolone drugs. Synopses of individual reports on adverse drug reactions are included, as are examples of various drug formulations on the market.

Dr Willmann Liang

Antibiotics that target bacterial nucleic acids: fluoroquinolones

Part of this narrated video (from 3:08 to 4:43) gives an overview of the mechanisms of action of fluoroquinolones.  Mechanisms of drug resistance are also briefly introduced.

Intermediate level.

Author: MedLecturesMadeEasy

No votes yet

Bacteria replicate DNA via a unique enzyme called DNA gyrase (or topoisomerase II). DNA at the replication fork exist in a positively-supercoiled arrangement and the structure is strained. DNA gyrase nicks one strand of the DNA (say at a supercoiled segment behind) and reseals the strand after it un-coils at the front. This process restores the usual, negatively-supercoiled and stabilised, unstrained state. Another enzyme, topoisomerase IV, acts to untangle the newly replicated DNA. Both topoisomerases II & IV can be inhibited by fluoroquinolones, but activity against topoisomerase II is more clinically relevant at present.

Ciprofloxacin is a representative example of fluoroquinolones, so named because compounds in the class possess a fluorine. Fluoroquinolones inhibit the activity of DNA gyrase, thus stopping DNA replication. Drugs in this class should be avoided in pregnant women (concerning fetus) and those under age 18 as the developing bones and cartilage will be affected. Unwanted effects are infrequent and mild, but ciprofloxacin is a known cytochrome P450 inhibitor. Thus, interactions with other P450 inhibitors such as theophylline can produce CNS effects such as headache, dizziness and convulsions.

Fluoroquinolones have a broad spectrum of antibacterial activity, but usage is best reserved for Gram-negative (Gm-) bacteria, including against Acinetobacter baumannii & Pseudomonas aeruginosa (combined with aminoglycoside), Haemophilus influenzae, enterobacteria (Enterobacter, E. coli, K. pneumoniae). Resistance to fluoroquinolones may arise most commonly when the structure of DNA gyrase is altered. This may result in weaker drug-binding or a binding site that is shielded from the drug. It should also be noted that inactivation by acetylation occurs via an enzyme that does the same to aminoglycosides.

Links to PubChem entries: ciprofloxacin (a second-generation fluoroquinolone); levoflaxacin (a third-generation fluoroquinolone); moxifloxacin (a fourth-generation fluoroquinolone). These entries list the key physico-chemical and pharmacological properties of these fluoroquinolone drugs. Synopses of individual reports on adverse drug reactions are included, as are examples of various drug formulations on the market.

Dr Willmann Liang

Fluoroquinolones: Mechanisms of action and resistance

This is a 7-minute animation showing the mechanism of action of the fluoroquinolones. Students will gain the most from this animation if they have an understanding of DNA replication.  A brief introduction of this process is also given in the first part of this video.  From 5:32 onward, mechanisms of resistance to fluoroquinolones are described, with reference to altered drug targets.  This video would be useful together with other resources related to the comprehensive pharmacology of the quinolones.

Advanced level

Author: Mechanisms in Medicine

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Bacteria replicate DNA via a unique enzyme called DNA gyrase (or topoisomerase II). DNA at the replication fork exist in a positively-supercoiled arrangement and the structure is strained. DNA gyrase nicks one strand of the DNA (say at a supercoiled segment behind) and reseals the strand after it un-coils at the front. This process restores the usual, negatively-supercoiled and stabilised, unstrained state. Another enzyme, topoisomerase IV, acts to untangle the newly replicated DNA. Both topoisomerases II & IV can be inhibited by fluoroquinolones, but activity against topoisomerase II is more clinically relevant at present.

Ciprofloxacin is a representative example of fluoroquinolones, so named because compounds in the class possess a fluorine. Fluoroquinolones inhibit the activity of DNA gyrase, thus stopping DNA replication. Drugs in this class should be avoided in pregnant women (concerning fetus) and those under age 18 as the developing bones and cartilage will be affected. Unwanted effects are infrequent and mild, but ciprofloxacin is a known cytochrome P450 inhibitor. Thus, interactions with other P450 inhibitors such as theophylline can produce CNS effects such as headache, dizziness and convulsions.

Fluoroquinolones have a broad spectrum of antibacterial activity, but usage is best reserved for Gram-negative (Gm-) bacteria, including against Acinetobacter baumannii & Pseudomonas aeruginosa (combined with aminoglycoside), Haemophilus influenzae, enterobacteria (Enterobacter, E. coli, K. pneumoniae). Resistance to fluoroquinolones may arise most commonly when the structure of DNA gyrase is altered. This may result in weaker drug-binding or a binding site that is shielded from the drug. It should also be noted that inactivation by acetylation occurs via an enzyme that does the same to aminoglycosides.

Links to PubChem entries: ciprofloxacin (a second-generation fluoroquinolone); levoflaxacin (a third-generation fluoroquinolone); moxifloxacin (a fourth-generation fluoroquinolone). These entries list the key physico-chemical and pharmacological properties of these fluoroquinolone drugs. Synopses of individual reports on adverse drug reactions are included, as are examples of various drug formulations on the market.

Dr Willmann Liang

Fluoroquinolones

This article provides an overview of the general pharmacology of fluoroquinolones.  Important unwanted effects are also described in detail.  A note is included about restricted fluoroquinolone use in the USA due to the adverse drug effects.

Advanced level

Author: David C Hooper

Note that Institutional subscription may be required to access UpToDate.com articles.

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Bacteria replicate DNA via a unique enzyme called DNA gyrase (or topoisomerase II). DNA at the replication fork exist in a positively-supercoiled arrangement and the structure is strained. DNA gyrase nicks one strand of the DNA (say at a supercoiled segment behind) and reseals the strand after it un-coils at the front. This process restores the usual, negatively-supercoiled and stabilised, unstrained state. Another enzyme, topoisomerase IV, acts to untangle the newly replicated DNA. Both topoisomerases II & IV can be inhibited by fluoroquinolones, but activity against topoisomerase II is more clinically relevant at present.

Ciprofloxacin is a representative example of fluoroquinolones, so named because compounds in the class possess a fluorine. Fluoroquinolones inhibit the activity of DNA gyrase, thus stopping DNA replication. Drugs in this class should be avoided in pregnant women (concerning fetus) and those under age 18 as the developing bones and cartilage will be affected. Unwanted effects are infrequent and mild, but ciprofloxacin is a known cytochrome P450 inhibitor. Thus, interactions with other P450 inhibitors such as theophylline can produce CNS effects such as headache, dizziness and convulsions.

Fluoroquinolones have a broad spectrum of antibacterial activity, but usage is best reserved for Gram-negative (Gm-) bacteria, including against Acinetobacter baumannii & Pseudomonas aeruginosa (combined with aminoglycoside), Haemophilus influenzae, enterobacteria (Enterobacter, E. coli, K. pneumoniae). Resistance to fluoroquinolones may arise most commonly when the structure of DNA gyrase is altered. This may result in weaker drug-binding or a binding site that is shielded from the drug. It should also be noted that inactivation by acetylation occurs via an enzyme that does the same to aminoglycosides.

Links to PubChem entries: ciprofloxacin (a second-generation fluoroquinolone); levoflaxacin (a third-generation fluoroquinolone); moxifloxacin (a fourth-generation fluoroquinolone). These entries list the key physico-chemical and pharmacological properties of these fluoroquinolone drugs. Synopses of individual reports on adverse drug reactions are included, as are examples of various drug formulations on the market.

Dr Willmann Liang

Fluoroquinolones

Part of this narrated video (from 19:34 to 22:08) introduces examples of different generations of fluoroquinolones. Their spectra of antibacterial activity are compared.

Author: Eric Strong

Advanced level 

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Bacteria replicate DNA via a unique enzyme called DNA gyrase (or topoisomerase II). DNA at the replication fork exist in a positively-supercoiled arrangement and the structure is strained. DNA gyrase nicks one strand of the DNA (say at a supercoiled segment behind) and reseals the strand after it un-coils at the front. This process restores the usual, negatively-supercoiled and stabilised, unstrained state. Another enzyme, topoisomerase IV, acts to untangle the newly replicated DNA. Both topoisomerases II & IV can be inhibited by fluoroquinolones, but activity against topoisomerase II is more clinically relevant at present.

Ciprofloxacin is a representative example of fluoroquinolones, so named because compounds in the class possess a fluorine. Fluoroquinolones inhibit the activity of DNA gyrase, thus stopping DNA replication. Drugs in this class should be avoided in pregnant women (concerning fetus) and those under age 18 as the developing bones and cartilage will be affected. Unwanted effects are infrequent and mild, but ciprofloxacin is a known cytochrome P450 inhibitor. Thus, interactions with other P450 inhibitors such as theophylline can produce CNS effects such as headache, dizziness and convulsions.

Fluoroquinolones have a broad spectrum of antibacterial activity, but usage is best reserved for Gram-negative (Gm-) bacteria, including against Acinetobacter baumannii & Pseudomonas aeruginosa (combined with aminoglycoside), Haemophilus influenzae, enterobacteria (Enterobacter, E. coli, K. pneumoniae). Resistance to fluoroquinolones may arise most commonly when the structure of DNA gyrase is altered. This may result in weaker drug-binding or a binding site that is shielded from the drug. It should also be noted that inactivation by acetylation occurs via an enzyme that does the same to aminoglycosides.

Links to PubChem entries: ciprofloxacin (a second-generation fluoroquinolone); levoflaxacin (a third-generation fluoroquinolone); moxifloxacin (a fourth-generation fluoroquinolone). These entries list the key physico-chemical and pharmacological properties of these fluoroquinolone drugs. Synopses of individual reports on adverse drug reactions are included, as are examples of various drug formulations on the market.

Dr Willmann Liang

Fluoroquinolones

This short video (6:55) is part of an introductory series of videos on antibiotic classes produced by Ryan Sheehy of Kansas City University. It uses a narrated animation to introduce you to the basic structure, mechanisms of action and clinical uses of fluoroquinolones. Commonly used drugs in this class include ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin. The fluoroquinolones are a family of broad spectrum, systemic antibacterial agents that have been used widely as therapy of respiratory and urinary tract infections. Fluoroquinolones are active against a wide range of aerobic gram-positive (Staphylococci, Streptococcus pneumoniae and viridans, Enterococcus faecalis, Listeria monocytogenes, and Nocardia) and gram-negative organisms (Neisseria meningitides and gonorrhoeae, Haemophilus influenzae, and most clinically important Enterobacteriaceae species). The fluoroquinolones probably act by inhibition of type II DNA toposiomerases (gyrases) that are required for synthesis of bacterial mRNAs (transcription) and DNA replication.

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Sulphonamides & trimethoprim (CO-trimoxazole)

Bacteria must generate their own precursors to nucleic acids. Para-aminobenzoic acid (PABA), together with a pteridine derivative and glutamic acid are needed to synthesise these precursors. The first step is catalysed by dihydropteroate synthetase (DHPS) to generate dihydropteric acid. A second enzyme, dihydrofolate synthetase (DHFS), adds glutamic acid and produces dihydrofolic acid. The last step, via dihydrofolate reductase (DHFR), yields tetrahydrofolic acid (THF). THF is then utilised in other pathways to generate nucleic acids. Notable unwanted effects of sulphonamides include photosensitivity, topical hypersensitivity and in severe cases, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Sulfonamides are compounds that possess a structure similar to PABA. These PABA analogues compete with the authentic PABA for DHPS, thus suppressing dihydropteroic acid production, and subsequently less THF is produced. Humans can obtain THF from diet, so blocking DHPS only affects bacteria. In fact, humans do not have DHPS. Trimethoprim is a pteridine analogue that blocks the activity of DHFR. Humans have DHFR, but trimethoprim is much more potent to bacterial DHFR. Trimethoprim is often given together with a sulphonamide (commonly sulfomethoxazole). The combined formulation is called co-trimoxazol. Co-trimoxazole interferes with THF synthesis at two points, i.e. concomittant inhibition of both DHPS and DHFR. The combined form serves to potentiate drug effect. Drug resistance is also less likely to be a problem as the susceptible bacteria are under attack at two points of the same biochemical pathway.

Long-term use of co-trimoxazole may bring about the expected unwanted effect of folate deficiency if dietary intake is below normal. Co-trimoxazole has a broad spectrum of antibacterial activity, but enterococci and P. aeruginosa are intrinsically resistant.

Co-trimoxazole can be used against methicillin-resistant Staphylococcus aureus (MRSA) together with drainage, as well as against extended-spectrum beta-lactamase-producing (ESBL+) E. coli and Klebsiella pneumoniae infections in the urinary tract. Resistance to co-trimoxazole may come in several forms. More commonly, bacteria may possess the ability to produce large amounts of PABA or DHFR, thereby the drugs are rendered useless. Another common mechanism is mutations causing alterations in the drug-binding site(s) of DHPS or DHFR and decreased drug affinity.

Dr Willmann Liang

Stop motion animation of co-trimoxazole mechanism of action

This un-narrated clay animation highlights the inhibitory effects of co-trimoxazole on DHPS and DHFR, thus preventing the conversion of PABA to dihydrofolic acid and tetrahydrofolic acid. Suitable for begginers.

Author: Joshua Shafer

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Bacteria must generate their own precursors to nucleic acids. Para-aminobenzoic acid (PABA), together with a pteridine derivative and glutamic acid are needed to synthesise these precursors. The first step is catalysed by dihydropteroate synthetase (DHPS) to generate dihydropteric acid. A second enzyme, dihydrofolate synthetase (DHFS), adds glutamic acid and produces dihydrofolic acid. The last step, via dihydrofolate reductase (DHFR), yields tetrahydrofolic acid (THF). THF is then utilised in other pathways to generate nucleic acids. Notable unwanted effects of sulphonamides include photosensitivity, topical hypersensitivity and in severe cases, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Sulfonamides are compounds that possess a structure similar to PABA. These PABA analogues compete with the authentic PABA for DHPS, thus suppressing dihydropteroic acid production, and subsequently less THF is produced. Humans can obtain THF from diet, so blocking DHPS only affects bacteria. In fact, humans do not have DHPS. Trimethoprim is a pteridine analogue that blocks the activity of DHFR. Humans have DHFR, but trimethoprim is much more potent to bacterial DHFR. Trimethoprim is often given together with a sulphonamide (commonly sulfomethoxazole). The combined formulation is called co-trimoxazol. Co-trimoxazole interferes with THF synthesis at two points, i.e. concomittant inhibition of both DHPS and DHFR. The combined form serves to potentiate drug effect. Drug resistance is also less likely to be a problem as the susceptible bacteria are under attack at two points of the same biochemical pathway.

Long-term use of co-trimoxazole may bring about the expected unwanted effect of folate deficiency if dietary intake is below normal. Co-trimoxazole has a broad spectrum of antibacterial activity, but enterococci and P. aeruginosa are intrinsically resistant.

Co-trimoxazole can be used against methicillin-resistant Staphylococcus aureus (MRSA) together with drainage, as well as against extended-spectrum beta-lactamase-producing (ESBL+) E. coli and Klebsiella pneumoniae infections in the urinary tract. Resistance to co-trimoxazole may come in several forms. More commonly, bacteria may possess the ability to produce large amounts of PABA or DHFR, thereby the drugs are rendered useless. Another common mechanism is mutations causing alterations in the drug-binding site(s) of DHPS or DHFR and decreased drug affinity.

Dr Willmann Liang

Antibiotics that target bacterial nucleic acids: co-trimoxazole

The first part of this video (up to 3:08) gives a more detailed overview of bacterial nucleic acid synthesis, and how this process is inhibited by co-trimoxazole.  Mechanisms of drug resistance are also briefly introduced.

Intermediate level.

Author: MedLecturesMadeEasy

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Bacteria must generate their own precursors to nucleic acids. Para-aminobenzoic acid (PABA), together with a pteridine derivative and glutamic acid are needed to synthesise these precursors. The first step is catalysed by dihydropteroate synthetase (DHPS) to generate dihydropteric acid. A second enzyme, dihydrofolate synthetase (DHFS), adds glutamic acid and produces dihydrofolic acid. The last step, via dihydrofolate reductase (DHFR), yields tetrahydrofolic acid (THF). THF is then utilised in other pathways to generate nucleic acids. Notable unwanted effects of sulphonamides include photosensitivity, topical hypersensitivity and in severe cases, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Sulfonamides are compounds that possess a structure similar to PABA. These PABA analogues compete with the authentic PABA for DHPS, thus suppressing dihydropteroic acid production, and subsequently less THF is produced. Humans can obtain THF from diet, so blocking DHPS only affects bacteria. In fact, humans do not have DHPS. Trimethoprim is a pteridine analogue that blocks the activity of DHFR. Humans have DHFR, but trimethoprim is much more potent to bacterial DHFR. Trimethoprim is often given together with a sulphonamide (commonly sulfomethoxazole). The combined formulation is called co-trimoxazol. Co-trimoxazole interferes with THF synthesis at two points, i.e. concomittant inhibition of both DHPS and DHFR. The combined form serves to potentiate drug effect. Drug resistance is also less likely to be a problem as the susceptible bacteria are under attack at two points of the same biochemical pathway.

Long-term use of co-trimoxazole may bring about the expected unwanted effect of folate deficiency if dietary intake is below normal. Co-trimoxazole has a broad spectrum of antibacterial activity, but enterococci and P. aeruginosa are intrinsically resistant.

Co-trimoxazole can be used against methicillin-resistant Staphylococcus aureus (MRSA) together with drainage, as well as against extended-spectrum beta-lactamase-producing (ESBL+) E. coli and Klebsiella pneumoniae infections in the urinary tract. Resistance to co-trimoxazole may come in several forms. More commonly, bacteria may possess the ability to produce large amounts of PABA or DHFR, thereby the drugs are rendered useless. Another common mechanism is mutations causing alterations in the drug-binding site(s) of DHPS or DHFR and decreased drug affinity.

Dr Willmann Liang

PubChem CID 358641

Key physico-chemical and pharmacological properties of co-trimoxazole are listed under this PubChem entry. Synopses of individual reports on adverse drug reactions are included. Examples of various co-trimoxazole formulations on the market are also provided.

 

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Bacteria must generate their own precursors to nucleic acids. Para-aminobenzoic acid (PABA), together with a pteridine derivative and glutamic acid are needed to synthesise these precursors. The first step is catalysed by dihydropteroate synthetase (DHPS) to generate dihydropteric acid. A second enzyme, dihydrofolate synthetase (DHFS), adds glutamic acid and produces dihydrofolic acid. The last step, via dihydrofolate reductase (DHFR), yields tetrahydrofolic acid (THF). THF is then utilised in other pathways to generate nucleic acids. Notable unwanted effects of sulphonamides include photosensitivity, topical hypersensitivity and in severe cases, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Sulfonamides are compounds that possess a structure similar to PABA. These PABA analogues compete with the authentic PABA for DHPS, thus suppressing dihydropteroic acid production, and subsequently less THF is produced. Humans can obtain THF from diet, so blocking DHPS only affects bacteria. In fact, humans do not have DHPS. Trimethoprim is a pteridine analogue that blocks the activity of DHFR. Humans have DHFR, but trimethoprim is much more potent to bacterial DHFR. Trimethoprim is often given together with a sulphonamide (commonly sulfomethoxazole). The combined formulation is called co-trimoxazol. Co-trimoxazole interferes with THF synthesis at two points, i.e. concomittant inhibition of both DHPS and DHFR. The combined form serves to potentiate drug effect. Drug resistance is also less likely to be a problem as the susceptible bacteria are under attack at two points of the same biochemical pathway.

Long-term use of co-trimoxazole may bring about the expected unwanted effect of folate deficiency if dietary intake is below normal. Co-trimoxazole has a broad spectrum of antibacterial activity, but enterococci and P. aeruginosa are intrinsically resistant.

Co-trimoxazole can be used against methicillin-resistant Staphylococcus aureus (MRSA) together with drainage, as well as against extended-spectrum beta-lactamase-producing (ESBL+) E. coli and Klebsiella pneumoniae infections in the urinary tract. Resistance to co-trimoxazole may come in several forms. More commonly, bacteria may possess the ability to produce large amounts of PABA or DHFR, thereby the drugs are rendered useless. Another common mechanism is mutations causing alterations in the drug-binding site(s) of DHPS or DHFR and decreased drug affinity.

Dr Willmann Liang

Trimethoprim-sulfamethoxazole: an overview

This article provides specific information on how and where resistance to co-trimoxazole may arise.  Common unwanted effects are also described in greater detail.

Advanced level.

Author: D Byron May

Note that Institutional subscription may be required to access UpToDate.com articles.

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Drugs for HIV infections

HIV medications are generally classified according to their mechanistic action.

The main classes are:

  • Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
  • Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
  • Protease Inhibitors (PIs)
  • Entry (or Fusion) Inhibitors
  • Integrase Inhibitors (or integrase strand transfer inhibitors (INSTIs))

 

NRTIs

NRTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses. Viral reverse transcriptase copies the single stand of the HIV’s RNA genome creating a double-stranded viral DNA that is able to integrate into the host chromosomal DNA. Host transcription and translation are hijacked to reproduce the virus. This group of drugs are analogues of the host’s endogenous deoxynucleotides that are required to synthesize viral DNA, but when incorporated in to a growing DNA molecule they block further elongation, acting as chain terminators. Drugs of this type can be either nucleoside or nucleotide analogues, with the former requiring kinase-mediated phosphorylation to generate active triphosphate molecules. Nucleoside reverse transcriptase inhibitors were the first type of ART drugs to be developed.

Examples include:

    Abacavir, or ABC (Ziagen)

    Didanosine, or ddl (Videx)

    Emtricitabine, or FTC (Emtriva)

    Lamivudine, or 3TC (Epivir)

    Stavudine, or d4T (Zerit)

    Tenofovir, or TDF (Viread)

    Zidovudine, or AZT or ZDV (Retrovir)

 

NNRTIs

NNRTIs bind directly to the viral reverse transcriptase and inhibit its activity. This action prevents viral replication.

    Delavirdine (Rescriptor)

    Doravirine (Pifeltro)

    Efavirenz (Sustiva)

    Etravirine (Intelence)

    Nevirapine (Viramune)

    Rilpivirine (Edurant)

 

PIs

HIV protease inhibitors are peptidomimetics that competitively inhibit the action of the virus' aspartyl protease, an enzyme crucial for the proteolytic cleavage of nascent polypeptide precursors into mature viral proteins.

    Atazanavir, or ATV (Reyataz)

    Darunavir, or DRV (Prezista)

    Fosamprenavir, or FPV (Lexiva)

    Indinavir, or IDV (Crixivan)

    Lopinavir + ritonavir, or LPV/r (Kaletra)

    Nelfinavir, or NFV (Viracept)

    Ritonavir, or RTV (Norvir)

    Saquinavir, or SQV (Invirase)

    Tipranavir, or TPV (Aptivus)

Cobicistat (Tybost) is an adjuvant drug that increases atazanavir and darunavir efficacy, but it can cause life-threatening kidney problems if it is adminstered with certain other medicines.

    Atazanavir + cobicistat, or ATV/COBI (Evotaz)

    Darunavir + cobicistat, or DRV/COBI (Prezcobix)

These first three groups of drugs work at the level of the HIV infected cell to inhibit viral replication.

 

The next groups of drugs have different mechanisms of action.

 

Entry (or Fusion) Inhibitors

Drugs of this class block viral fusion and entry to the T cells.

Enfuvirtide, or ENF or T-20 (Fuzeon), is a biomimetic peptide that binds to the viral transmembrane protein gp41, and inhibits formation of the entry pore that is required for the capsid of the virus to enter the cell. Enfuvirtide is active against HIV-1, with very low activity against HIV-2. Enfuvirtide is delivered by injection, so adherence may be an issue for some patients.

In March 2018, the US FDA approved a first-in-class treatment for heavily treatment-experienced patients with multidrug resistant HIV, who have limited treatment options. Ibalizumab-uiyk (proprietary name Trogarzo; IMGT link) is an anti-CD4 monoclonal antibody that inhibits the viral entry process (see Jacobson et al. (2009)), and is able to block CCR5- and CXCR4-tropic viruses. It is non-immunosuppressive. Ibalizumab-uiyk is administered iv once/2 weeks by a medical professional, and should be used in combination with an optimized background regimen of other antiretroviral drugs.  

 

CCR5 Antagonist

Drugs with this action are also entry inhibitors, but with a distinct mechanism of action compared to enfuvirtide. The CCR5 chemokine receptor is an important co-receptor that HIV-1 uses to attach to cells before viral fusion and entry into host cells. Maraviroc (MVC, Selzentry) is a CCR5 antagonist that inhibits the HIV-CCR5 interaction and thereby prevents HIV from entering the cells. Many treatment-experienced patients may have non-CCR5-tropic virus. Thus, screening patients with tropism assays (e.g. Trofile) before maraviroc initiation is essential.

 

Integrase Inhibitors

Integrase is a key viral enzyme that facilitates integration of retroviral DNA into the host cell genome. Drugs of this family inhibit this process, thereby preventing viral replication.

    Bictegravir

    Dolutegravir (Tivicay)

    Elvitegravir (Vitekta)

    Raltegravir (Isentress)

 

Fixed-Dose combination HIV medications

    Bictegravir + embitcitabine + tenofovir alafenamide, or BIC/FTC/TAF (Biktarvy)

    Abacavir + dolutegravir + lamivudine, or ABC/DTG/3TC (Triumeq)

    Abacavir + lamivudine, or ABC/3TC (Epzicom)

    Abacavir + lamivudine + zidovudine, or ABC/3TC/ZDV (Trizivir)

    Doravirine + lamivudine + tenofovir disoproxil fumarate (Delstrigo)

    Efavirenz + emtricitabine + tenofovir, or EFV/FTC/TDF (Atripla, Tribuss)

    Elvitegravir + cobicistat + emtricitabine + tenofovir, or EVG/COBI/FTC/TAF or ECF/TAF (Genvoya)

    Elvitegravir + cobicistat + emtricitabine + tenofovir, or EVG/COBI/FTC/TDF or ECF/TDF (Stribild)

    Emtricitabine + rilpivirine + tenofovir, or FTC/RPV/TAF (Odefsey)

    Emtricitabine + rilpivirine + tenofovir, or FTC/RPV/TDF (Complera)

    Emtricitabine + tenofovir, or TAF/FTC (Descovy)

    Dolutegravir + lamivudine or DTG/3TC (Dovato)

    Emtricitabine + tenofovir, or TDF/FTC (Truvada)

    Lamivudine + zidovudine, or 3TC/ZDV (Combivir)

 

ART adherence is essential to prevent drug-resistant strains of HIV developing. If ART is used properly HIV-positive patients can now live long, active lives.

Prescribing decisions are reached by considering existing medical conditions, immune system function, and should involve discussions about which regimen the patient would prefer, and would be most likely to adhere to.

 

Pre-exposure prophylaxis (or PrEP) is the most recent advance in ART, with the approval of Truvada as a therapy to reduce the likelihood of HIV infection in high risk individuals (e.g. to reduce the risk of HIV-negative people getting HIV from a sexual or injection-drug-using partner who is HIV-positive). The CDC (https://www.cdc.gov/hiv/basics/prep.html) reported that among people who inject drugs, PrEP reduces infection risk by >70%. If combined with ‘safe sex’ the risk of getting sexually transmitted HIV whilst taking PrEP is reduced by up to 90%.

immunopaedia.org.za

This is an immunology website based in South Africa, in partnership with the International Union of Immunological Societies (IUIS), that has a strong emphasis on HIV and AIDS. The website offers Teaching and Learning Tools (including core immunology modules) as well as a Treatment & Diagnostics section that includes HIV-specific topics such as HIV Life Cycle, Declining CD4 count and ARV Drug Information.

Average: 3 (5 votes)

Drugs for viral hepatitis- HBV and HCV

Hepatitis B

Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV). It can cause both acute and chronic infections. Most cases of chronic disease are asymptomatic, however, cirrhosis and liver cancer may eventually develop. HBV is transmitted by exposure to infectious blood or body fluids. The infection can be diagnosed 30 to 60 days after exposure. HBV infection has been preventable by vaccination since 1982, with two or three doses required to achieve full protection. Natural life-long resistance develops following infection.

During initial infection, care is based on the patient’s symptoms. As an exception, early antiretroviral therapy may be indicated for cases of aggressive (fulminant) hepatitis or when the patient is immunocompromised. In those who develop chronic disease, antiviral medication such as tenofovir or interferon may be useful to reduce the risk of cirrhosis and liver cancer. The drugs available cannot clear the infection, rather they inhibit viral replication to limit liver damage. The World Health Organization recommended a combination of tenofovir and entecavir as first-line agents.

Drugs approved for HBV infection include

adefovir (Hepsera)

entecavir (Baraclude)

lamivudine (Epivir)

telbivudine (Tyzeka)

tenofovir (Viread)

and the two immune system modulators interferon alpha-2a and PEGylated interferon alpha-2a (Pegasys)

 

Hepatitis C

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV). Few symptoms are evident during the initial period of infection, or even when disease has progressed to early chronic infection. Damage accumulates over time and can lead to liver disease, cirrhosis and liver cancer. HCV is spread primarily by blood-to-blood contact (e.g. associated with intravenous drug use, poorly sterilized medical equipment, needlestick injuries in healthcare, blood transfusions, and mother-to-child transmission).

There is no vaccine against hepatitis C, however chronic HCV infection can be effectively managed about 95% of the time with antiviral medications. HCV treatment focusses on management rather than cure. Treatment aims are:

  • eradication of virus
  • decreasing morbidity and mortality
  • normalization of biochemical markers
  • improving clinical symptoms
  • preventing spread of the disease
  • preventing progression to cirrhosis and hepatocellular carcinoma
  • preventing the development of end-stage liver disease and its manifestations

 

How do anti-HCV drugs work?

See further analysis of 'The ins and outs of hepatitis C virus entry and assembly' by Lindenbach and Rice (2013) PMID: 24018384

 

Direct-acting hepatitis C virus antiviral agents

Ledipasvir inhibits the HCV NS5A protein necessary for viral replication.

Ombitasvir is an HCV NS5A replication complex inhibitor, and interferes with viral RNA replication and virion assembly.

Pibrentasvir is a NS5A Inhibitor (prescribed in a fixed-dose formulation with glecaprevir).

Paritaprevir inhibits HCV NS3/4A protease and interferes with HCV coded polyprotein cleavage necessary for viral replication.

Glecaprevir is also a NS3/4A protease inhibitor (prescribed in a fixed-dose formulation with pibrentasvir).

Ribavirin is a synthetic nucleoside analogue with antiviral activity. It MUST be used in combination with an interferon product. Ribavirin monotherapy is not effective for the treatment of chronic HCV infection and should not be used alone for this indication. The mechanism by which the combination of ribavirin + interferon exerts its anti-HCV effects has not been fully established.

Simeprevir, like ribavirin is not effective as a monotherapy, and must be used in combination with peginterferon alfa and ribavirin, or with sofosbuvir. Mechanistically, simeprevir is an inhibitor of HCV NS3/4A protease, a protease that is essential for viral replication.

Sofosbuvir is a prodrug converted to its pharmacologically active form (GS-461203, a nucleoside (uridine) analog triphosphate) that acts as an inhibitor of HCV NS5B RNA-dependent RNA polymerase, acting as a chain terminator during viral replication.

Velpatasvir is an HCV NS5A replication complex inhibitor, and interferes with viral RNA replication and virion assembly.

Voxilaprevir is an inhibitor of HCV NS3/4A protease, a protease that is essential for viral replication.

Indirect anti-HCV drugs

Ritonavir is not active against HCV directly. Ritonavir is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of paritaprevir and overall drug exposure (i.e. AUC).

 

There are at least six genetically distinct HCV genotypes, or strains. Knowing the strain of the virus can help inform treatment recommendations. Treatment during the first six months is more effective than once chronic infection has established.

HCV genotypes
HCV genotype Recommended treatment regimen Alternative treatment regimen
1a 12 weeks of ledipasvir + sofosbuvir 12 to 24 weeks of paritaprevir + ombitasvir + dasabuvir + ribavirin
1b 12 weeks of ledipasvir + sofosbuvir 12 weeks of paritaprevir + ombitasvir + dasabuvir
2 12 to 16 weeks of sofosbuvir and ribavirin  
3 12 weeks of sofosbuvir + ribavirin + pegylated interferon  
4 12 weeks of ledipasvir + sofosbuvir or paritaprevir + ritonavir + ombitasvir + ribavirin 24 weeks of sofosbuvir + ribavirin
5 or 6 sofosbuvir + ledipasvir  

Recommendations based on AASLD/IDSA HCV Guidance, Panel (September 2015). PMID 26111063

  • sofosbuvir + ribavirin + interferon is ~90% effective in those with genotype 1, 4, 5, or 6 disease
  • sofosbuvir + ribavirin is 70-95% effective in type 2 and 3 disease but has a higher rate of adverse effects.
  • ledipasvir + sofosbuvir for genotype 1 is 93-99% effective but is very expensive
  • pegylated interferon + ribavirin- is 60-90% effective in genotype 6 infection

Latest drug approvals:

Vosevi (FDA approval in July 2017), is a fixed-dose, combination tablet containing two previously approved drugs (sofosbuvir and velpatasvir), and a new drug, voxilaprevir. Approved for use in adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis or with mild cirrhosis, including re-treatment of patients previously treated with the direct-acting antiviral drug sofosbuvir or NS5A inhibitors. This new approval represents a treatment option for those patients who were not successfully treated with other HCV drugs. Treatment recommendations for Vosevi are different depending on viral genotype and prior treatment history. The most common adverse reactions are headache, fatigue, diarrhoea and nausea. Vosevi is contraindicated in patients taking the drug rifampin. Hepatitis B virus (HBV) reactivation is a potentially life-threatening Vosevi-associated event in HCV/HBV coinfected patients, so patients should be screened for evidence of current or prior HBV infection before starting treatment with Vosevi.

Mavyret (FDA approval in August 2017), is a fixed-dose, combination tablet containing glecaprevir and pibrentasvir. It's approved for the treatment of adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis. It is also approved for HCV genotype 1 infections in patients who have previously been treated with either a NS5A inhibitor or an NS3/4A protease inhibitor (but not both). The recommended treatment regimen is eight weeks, which is shorter than the previous therapies which were administered for 12 weeks.

Drugs for cytomegalovirus (CMV) infection

The anti-human CMV drugs used currently target CMV replication via two distinct mechansims.

pUL54 inhibitors

Ganciclovir (GCV; Cytovene) is a nucleoside analogue. It must be phosphorylated (to the nucleotide) by the viral protein kinase, pUL97 to confer anti-viral activity. Use of GCV as prophylaxis for CMV is limited by clinically significant myelosuppression. GCV is more commonly used to treat CMV retinitis, usually in patients who have suppressed immune systems (e.g. AIDS patients and solid organ transplant patients). It is also used to treat ocular ulcers caused by the herpes simplex virus.

Valganciclovir (Valcyte) is a GCV prodrug, that is generally used to prevent CMV reactivation or infection that may occur after a solid organ transplant. Like ganciclovir it causes significant myelosuppression.

Cidofovir (CDV), on the other hand is a nucleotide analogue, and does not need modification for activity. Cidofovir is only used to treat CMV retinitis in AIDS patients.

Foscarnet (FOS) inhibits pUL54 activity by binding to the enzyme's pyrophosphate binding site. It is used to treat CMV retinitis in AIDS patients and HSV infection in immunocompromised patients after failure to respond to other antiviral drugs.

Mutations in either pUL97 or pUL54 can result in resistance against these three drugs. Most cases of resistance to GCV are due to mutations in the UL97 gene, but mutations in the UL54 gene can also cause antiviral resistance. The problem of resistance to current drugs has been addressed by the development of compounds with an alternative mechanism to disrupt viral replication.

Viral terminase inhibitor

Letermovir (Prevymis) is the most recently approved anti-CMV medication (FDA approval granted in November 2017, and EMA marketing authorisation in January 2018). Letermovir inhibits the viral terminase complex (which consists of the CMV-encoded proteins pUL51, pUL56, and pUL89), which is a DNA packaging unit that is essential for DNA-containing viral capsid formation. By inhibiting terminase activity (by binding to pUL51 and/or pUL56), letermovir prevents CMV replication. This drug can be administerd orally or by i.v. infusion. It is approved as prophylaxis for CMV in allogeneic hematopoietic-cell transplantation patients who are receiving immunosuppressant therapy. It prevents CMV reactivation in these patients (see PMID: 29211658).

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