Penicillin Allergy and Cephalosporins
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Questions and Answers

What is the characteristic of true cephalosporins against gram-positive bacteria?

  • They have no activity
  • They have equivalent activity to first-generation agents (correct)
  • They have little activity
  • They have higher activity compared to first-generation agents

    • Which of the following bacteria is susceptible to second-generation cephalosporins?

  • Bacillus subtilis
  • Pseudomonas aeruginosa
  • Streptococcus pneumoniae
  • Neisseria spp. (correct)

    • Which of the following second-generation cephalosporins has little activity against gram-positive bacteria?

  • Cefuroxime
  • Cefotetan
  • Cefaclor
  • Cefoxitin (correct)

    • What is the activity of second-generation cephalosporins against Escherichia coli?

    <p>They have activity against it</p> Signup and view all the answers

    Which of the following bacteria is not susceptible to second-generation cephalosporins?

    <p>Pseudomonas aeruginosa</p> Signup and view all the answers

    What is the characteristic of cefotetan against gram-positive bacteria?

    <p>It has little activity</p> Signup and view all the answers

    What percentage of individuals allergic to penicillin are likely to react to cephalosporins?

    <p>5% to 10%</p> Signup and view all the answers

    Why should individuals with severe immediate hypersensitivity reactions to penicillin not be treated with cephalosporins?

    <p>Due to the risk of a severe allergic reaction</p> Signup and view all the answers

    What is a rare adverse effect of cephalosporins?

    <p>Reversible neutropenia</p> Signup and view all the answers

    What is a unique side effect of cefotetan?

    <p>Hypoprothrombinemia</p> Signup and view all the answers

    What is the route of excretion for ceftriaxone?

    <p>Biliary excretion</p> Signup and view all the answers

    Who discovered cephalosporins?

    <p>Giuseppe Brotzu</p> Signup and view all the answers

    What is the microbe that produces the inhibitory compound that led to the discovery of cephalosporins?

    <p>Cephalosporium acremonium</p> Signup and view all the answers

    What is the publication where the history of cephalosporins was documented?

    <p>The Cephalosporin Antibiotics</p> Signup and view all the answers

    What is the primary reason for the limited activity of first-generation cephalosporins against aerobic and facultative gram-negative bacteria?

    <p>Their side chains do not protect the β-lactam ring from cleavage by the β-lactamases of most gram-negative bacteria.</p> Signup and view all the answers

    Which of the following bacteria is first-generation cephalosporins effective against?

    <p>Staphylococcus aureus</p> Signup and view all the answers

    What is the mechanism by which first-generation cephalosporins protect against staphylococcal β-lactamases?

    <p>Their side chains protect the β-lactam ring from cleavage by staphylococcal β-lactamases.</p> Signup and view all the answers

    What is the characteristic of first-generation cephalosporins that limits their activity against anaerobes, intracellular bacteria, and spirochetes?

    <p>They have moderate to poor activity against these types of bacteria.</p> Signup and view all the answers

    Which of the following is a characteristic of first-generation cephalosporins that makes them useful in the treatment of infections?

    <p>They are useful in the treatment of infections caused by many strains of Staphylococcus aureus.</p> Signup and view all the answers

    Which of the following bacteria is not susceptible to first-generation cephalosporins?

    <p>MRSA</p> Signup and view all the answers

    How do carbapenems gain access to the PBPs in gram-negative bacteria?

    <p>Through special porins in the outer membrane</p> Signup and view all the answers

    What is a characteristic of carbapenems that makes them resistant to cleavage by beta-lactamases?

    <p>The structure of the five-membered ring</p> Signup and view all the answers

    What is the result of the small size and charge characteristics of carbapenems?

    <p>Enhanced ability to utilize special porins in the outer membrane</p> Signup and view all the answers

    What is a reason for the broad spectra of activity of carbapenems?

    <p>Their affinity for a broad range of PBPs</p> Signup and view all the answers

    How do the structures of carbapenems differ from those of penicillins?

    <p>Carbapenems have a five-membered ring with a double bond and a methylene group instead of sulfur</p> Signup and view all the answers

    What is a characteristic of carbapenems that makes them effective against many organisms?

    <p>Their broad affinity for PBPs</p> Signup and view all the answers

    What is the result of the combination of properties of carbapenems?

    <p>Incredibly broad spectra of activity</p> Signup and view all the answers

    What is the consequence of the unique structure of carbapenems?

    <p>Broad affinity for PBPs</p> Signup and view all the answers

    What is the mechanism by which cephamycins have enhanced stability to the β-lactamases of some anaerobes?

    <p>The presence of an additional methoxy group on the β-lactam ring</p> Signup and view all the answers

    What is the consequence of the additional methoxy group on the β-lactam ring of cephamycins?

    <p>Decreased activity against aerobic gram-positive bacteria</p> Signup and view all the answers

    What is the key feature that distinguishes second-generation cephalosporins from first-generation cephalosporins?

    <p>Increased potency against E. coli, K. pneumoniae, and P. mirabilis</p> Signup and view all the answers

    Which of the following is a characteristic of true cephalosporins?

    <p>Activity against aerobic and facultative gram-negative bacteria</p> Signup and view all the answers

    What is the advantage of second-generation cephalosporins over first-generation cephalosporins?

    <p>Improved activity against E. coli, K. pneumoniae, and P. mirabilis</p> Signup and view all the answers

    What is the reason for the limited activity of cephamycins against staphylococci and streptococci?

    <p>Due to their decreased affinity for the PBPs of these bacteria</p> Signup and view all the answers

    What is the result of the presence of an aminothiazolyl group at R1 in third-generation cephalosporins?

    <p>Increased penetration of the bacterial outer membrane, increased affinity for PBPs, and increased stability in the presence of some plasmid-encoded β-lactamases</p> Signup and view all the answers

    What is the mechanism by which third-generation cephalosporins inhibit bacterial growth?

    <p>By inhibiting the synthesis of the bacterial cell wall</p> Signup and view all the answers

    Which of the following bacteria is susceptible to third-generation cephalosporins?

    <p>All of the above</p> Signup and view all the answers

    What is the advantage of third-generation cephalosporins over second-generation cephalosporins?

    <p>Increased activity against E. coli, Klebsiella spp., and other Enterobacteriaceae</p> Signup and view all the answers

    What is the role of the aminothiazolyl group at R1 in third-generation cephalosporins?

    <p>It increases the affinity for PBPs</p> Signup and view all the answers

    What is the effect of third-generation cephalosporins on the bacterial outer membrane?

    <p>They increase the penetration of the bacterial outer membrane</p> Signup and view all the answers

    Which of the following is a characteristic of third-generation cephalosporins?

    <p>Moderate activity against aerobic gram-positive bacteria and increased activity against E. coli, Klebsiella spp., and other Enterobacteriaceae</p> Signup and view all the answers

    What is the result of the modification of the R1 position in third-generation cephalosporins?

    <p>Increased penetration of the bacterial outer membrane and increased affinity for PBPs</p> Signup and view all the answers

    How do some bacteria, such as P. aeruginosa, develop resistance to carbapenems?

    <p>By acquiring mutations that result in loss of production of the outer membrane porin</p> Signup and view all the answers

    What is a mechanism by which Enterococcus faecium and methicillin-resistant staphylococci are resistant to carbapenems?

    <p>They produce altered PBPs that do not bind these carbapenems</p> Signup and view all the answers

    What is a characteristic of carbapenems that makes them resistant to cleavage by β-lactamases?

    <p>Their small size and neutral charge</p> Signup and view all the answers

    What is the result of the combination of properties of carbapenems?

    <p>They are effective against a broad spectrum of bacteria</p> Signup and view all the answers

    What is a characteristic of some bacteria that have acquired resistance to carbapenems?

    <p>They produce extremely powerful β-lactamases</p> Signup and view all the answers

    What was the first commercially available carbapenem in the United States?

    <p>Imipenem</p> Signup and view all the answers

    What is the reason for the broad spectra of activity of carbapenems?

    <p>Their structure makes them resistant to cleavage by most β-lactamases</p> Signup and view all the answers

    How do carbapenems gain access to the PBPs in gram-negative bacteria?

    <p>Through the use of special porins in the outer membrane</p> Signup and view all the answers

    What is a characteristic of carbapenems that makes them resistant to cleavage by β-lactamases?

    <p>Their structure, which is related to that of penicillins and cephalosporins</p> Signup and view all the answers

    What is the result of the small size and charge characteristics of carbapenems?

    <p>They are able to utilize special porins in the outer membrane of gram-negative bacteria</p> Signup and view all the answers

    What is a characteristic of carbapenems that makes them effective against many organisms?

    <p>Their high affinity for a broad range of PBPs</p> Signup and view all the answers

    What is the result of the combination of properties of carbapenems?

    <p>They are resistant to β-lactamases and have a broad range of activity</p> Signup and view all the answers

    What is the consequence of the unique structure of carbapenems?

    <p>They are resistant to β-lactamases and have a broad range of activity</p> Signup and view all the answers

    What is the characteristic of carbapenems that makes them different from penicillins and cephalosporins?

    <p>They have a five-membered ring with a double bond and a methylene group instead of sulfur</p> Signup and view all the answers

    What is the weakness of ertapenem compared to other carbapenems?

    <p>It has a lower activity against aerobic gram-positive bacteria, P. aeruginosa, and Acinetobacter spp.</p> Signup and view all the answers

    Which of the following is a common adverse event associated with carbapenem use?

    <p>All of the above</p> Signup and view all the answers

    What is a characteristic of doripenem that distinguishes it from other carbapenems?

    <p>It is less likely to cause seizures</p> Signup and view all the answers

    Which of the following bacteria is resistant to all carbapenems?

    <p>Enterococcus faecium</p> Signup and view all the answers

    Why should patients with preexisting central nervous system disease and renal insufficiency be given carbapenems with caution?

    <p>Because they are more likely to experience seizures</p> Signup and view all the answers

    What is a characteristic of carbapenems that makes them effective against a broad spectrum of bacteria?

    <p>Their ability to inhibit cell wall synthesis</p> Signup and view all the answers

    What is the advantage of ertapenem compared to other carbapenems?

    <p>It requires only once per day dosing</p> Signup and view all the answers

    What is the characteristic of carbapenems that makes them resistant to cleavage by beta-lactamases?

    <p>Their small size and charge characteristics</p> Signup and view all the answers

    What is a characteristic of monobactams?

    <p>They consist of a lone β-lactam ring</p> Signup and view all the answers

    What is Aztreonam?

    <p>A totally synthetic monobactam</p> Signup and view all the answers

    What is similar to the R1 side chain of aztreonam?

    <p>The R1 side chain of ceftazidime</p> Signup and view all the answers

    What is the structure of aztreonam?

    <p>A single β-lactam ring with a specific R1 side chain</p> Signup and view all the answers

    What is a characteristic of monobactams compared to other β-lactam antibiotics?

    <p>They have a simpler ring structure</p> Signup and view all the answers

    What is the significance of the term 'monobactam'?

    <p>It refers to a type of antibiotic with a single β-lactam ring</p> Signup and view all the answers

    What is a unique feature of aztreonam that improves its activity against aerobic gram-negative bacteria?

    <p>Presence of an aminothiazolyl group</p> Signup and view all the answers

    Which of the following bacteria is NOT susceptible to aztreonam?

    <p>Gram-positive bacteria</p> Signup and view all the answers

    What is a common mechanism of resistance to aztreonam in some Enterobacteriaceae and P. aeruginosa?

    <p>Changes in permeability of the outer membrane</p> Signup and view all the answers

    What is a major advantage of aztreonam?

    <p>Safety profile</p> Signup and view all the answers

    What is a limitation of aztreonam?

    <p>Ineffective against gram-positive bacteria</p> Signup and view all the answers

    What is the effect of aztreonam on PBP binding?

    <p>It binds well to PBPs of aerobic gram-negative bacteria</p> Signup and view all the answers

    What is a characteristic of aztreonam that makes it effective against many gram-negative bacteria?

    <p>Stability against many beta-lactamases</p> Signup and view all the answers

    What is the activity of aztreonam against P. aeruginosa?

    <p>Intermediate activity</p> Signup and view all the answers

    What is the primary activity of aztreonam?

    <p>Against aerobic gram-negative bacteria</p> Signup and view all the answers

    What is a characteristic of aztreonam that makes it safe to use in certain patients?

    <p>It is safe to use in patients with penicillin allergies</p> Signup and view all the answers

    What is a advantage of aztreonam over aminoglycosides?

    <p>It is a renal-sparing alternative</p> Signup and view all the answers

    What is the only commercially available monobactam?

    <p>Aztreonam</p> Signup and view all the answers

    What is a limitation of aztreonam?

    <p>It is not effective against gram-positive bacteria or anaerobic bacteria</p> Signup and view all the answers

    What is a feature of aztreonam that makes it useful in certain patients?

    <p>It is safe to use in patients with allergies to other β-lactam agents</p> Signup and view all the answers

    What is a characteristic of aztreonam that distinguishes it from other β-lactam antibiotics?

    <p>It lacks cross-reactivity with other β-lactam antibiotics</p> Signup and view all the answers

    What is the activity of aztreonam against aerobic gram-negative bacteria?

    <p>Excellent</p> Signup and view all the answers

    What is the mechanism of action of vancomycin?

    <p>It binds to the d-alanyl–d-alanine dipeptide on the peptide side chain of newly synthesized peptidoglycan subunits</p> Signup and view all the answers

    What is the result of the substitution of d-alanyl–d-alanine with d-alanyl–d-lactate in vancomycin-resistant strains of enterococci?

    <p>The peptidoglycan subunit is appropriately incorporated into the cell wall</p> Signup and view all the answers

    What is the target of vancomycin in the bacterial cell wall?

    <p>The d-alanyl–d-alanine dipeptide</p> Signup and view all the answers

    What is the consequence of vancomycin binding to the d-alanyl–d-alanine dipeptide?

    <p>The peptidoglycan subunit is not incorporated into the cell wall</p> Signup and view all the answers

    What is the role of penicillin-binding proteins in the bacterial cell wall?

    <p>They incorporate peptidoglycan subunits into the cell wall</p> Signup and view all the answers

    What is the characteristic of vancomycin that makes it effective against certain bacteria?

    <p>It is a glycopeptide antibiotic</p> Signup and view all the answers

    What is the result of the substitution of d-alanyl–d-alanine with d-alanyl–d-lactate in vancomycin-resistant strains of enterococci?

    <p>Vancomycin is not effective against the bacteria</p> Signup and view all the answers

    What is the significance of the structure of vancomycin?

    <p>It allows vancomycin to bind to the d-alanyl–d-alanine dipeptide</p> Signup and view all the answers

    What is the characteristic of glycopeptide antibiotics that prevents them from passing through porins in the outer membranes of gram-negative bacteria?

    <p>Their large size</p> Signup and view all the answers

    What is the reason for the restricted activity of glycopeptide antibiotics to gram-positive organisms?

    <p>Their inability to penetrate the gram-negative outer membrane</p> Signup and view all the answers

    Which of the following bacteria is usually susceptible to glycopeptide antibiotics in vitro?

    <p>L.monocytogenes</p> Signup and view all the answers

    What is the route of administration of glycopeptide antibiotics?

    <p>Intravenous</p> Signup and view all the answers

    Which of the following bacteria is not susceptible to glycopeptide antibiotics?

    <p>Gram-negative bacteria</p> Signup and view all the answers

    What is the characteristic of vancomycin and telavancin that makes them effective against nearly all staphylococci and streptococci?

    <p>Their large size and sugar moieties</p> Signup and view all the answers

    Rifampin binds to which bacterial component and inhibits synthesis of?

    <p>RNA polymerase and inhibits RNA synthesis</p> Signup and view all the answers

    Rifampin is primarily used in the treatment of diseases caused by which organisms?

    <p>M. tuberculosis and M. leprae</p> Signup and view all the answers

    The rifamycins are usually used in conjunction with other antimicrobial agents because resistance to rifamycins develops during:

    <p>Monotherapy</p> Signup and view all the answers

    Aminoglycosides were initially active against both:

    <p>Gram-positive and gram-negative bacteria</p> Signup and view all the answers

    The aminoglycosides were first purified from the bacterium:

    <p>Streptomyces griseus</p> Signup and view all the answers

    Neomycin became available in which year?

    <p>1949</p> Signup and view all the answers

    Gentamicin was introduced in which year?

    <p>1963</p> Signup and view all the answers

    Amikacin was introduced in which year?

    <p>1972</p> Signup and view all the answers

    What is the characteristic of glycopeptide antibiotics?

    <p>They are extremely large molecules that cannot pass through porins in gram-negative bacteria.</p> Signup and view all the answers

    What is the scope of activity of vancomycin and telavancin?

    <p>They are active against nearly all staphylococci and streptococci, including methicillin-resistant staphylococci.</p> Signup and view all the answers

    Why are glycopeptide antibiotics usually given intravenously?

    <p>Because they are poorly absorbed in the gastrointestinal tract.</p> Signup and view all the answers

    What is the reason for the limited activity of glycopeptide antibiotics against gram-negative bacteria?

    <p>They are unable to pass through the outer membrane of gram-negative bacteria.</p> Signup and view all the answers

    What is the significance of the sugar moieties attached to glycopeptide antibiotics?

    <p>They are an essential component of the antibiotic's structure.</p> Signup and view all the answers

    What is the consequence of the large molecular structure of glycopeptide antibiotics?

    <p>They are restricted to activity against gram-positive organisms.</p> Signup and view all the answers

    What is the mechanism of action of Vancomycin?

    <p>Inhibition of cell wall synthesis by binding to d-alanyl–d-alanine dipeptide</p> Signup and view all the answers

    How do vancomycin-resistant strains of enterococci evade vancomycin?

    <p>By replacing d-alanyl–d-alanine dipeptide with d-alanyl–d-lactate</p> Signup and view all the answers

    What is the target of vancomycin in the cell wall?

    <p>D-alanyl–d-alanine dipeptide</p> Signup and view all the answers

    What is the result of vancomycin binding to the d-alanyl–d-alanine dipeptide?

    <p>Inhibition of cell wall synthesis</p> Signup and view all the answers

    What is the effect of vancomycin on peptidoglycan synthesis?

    <p>Inhibition of peptidoglycan synthesis</p> Signup and view all the answers

    What is the role of penicillin-binding proteins (PBPs) in cell wall synthesis?

    <p>Incorporation of peptidoglycan subunits into the cell wall</p> Signup and view all the answers

    What is the mechanism by which vancomycin prevents peptidoglycan subunits from being incorporated into the cell wall?

    <p>Binding to d-alanyl–d-alanine dipeptide</p> Signup and view all the answers

    What is the effect of vancomycin on bacterial growth?

    <p>Inhibition of bacterial growth</p> Signup and view all the answers

    What is the primary reason rifamycins are usually used in conjunction with other antimicrobial agents?

    <p>Because resistance to rifamycins develops during monotherapy</p> Signup and view all the answers

    What is the mechanism by which rifampin inhibits bacterial RNA polymerase?

    <p>By blocking the action of RNA polymerase</p> Signup and view all the answers

    Which of the following is NOT a characteristic of rifampin?

    <p>It is effective against viral infections</p> Signup and view all the answers

    What is the name of the first rifamycin antibiotic to be discovered?

    <p>Streptomycin</p> Signup and view all the answers

    What is the primary use of rifaximin?

    <p>Treatment of enteric infections</p> Signup and view all the answers

    What is a characteristic of aminoglycosides?

    <p>They are effective against both gram-negative and gram-positive bacteria</p> Signup and view all the answers

    What is the year in which gentamicin was introduced?

    <p>1963</p> Signup and view all the answers

    What is the name of the bacterium from which streptomycin was purified?

    <p>Streptomyces griseus</p> Signup and view all the answers

    What is the antimicrobial activity of daptomycin?

    <p>Against gram-positive bacteria and anaerobic bacteria</p> Signup and view all the answers

    Which bacteria is susceptible to daptomycin?

    <p>Staphylococci and Enterococci</p> Signup and view all the answers

    What is the characteristic of daptomycin?

    <p>It is a novel antibiotic for treating infections due to drug-resistant gram-positive pathogens</p> Signup and view all the answers

    What is the recent trend in the use of colistin?

    <p>It has become a popular choice for clinicians</p> Signup and view all the answers

    Why did colistin fall into disfavor in the early 1980s?

    <p>Due to its perceived toxicities and the availability of safer alternatives</p> Signup and view all the answers

    What is the reason for the renewed interest in colistin?

    <p>Due to the increasing resistance of gram-negative bacteria to other antibiotics</p> Signup and view all the answers

    What is the activity of daptomycin against anaerobic bacteria?

    <p>It has good activity</p> Signup and view all the answers

    What is the scope of daptomycin's antimicrobial activity?

    <p>Broad spectrum against gram-positive bacteria and anaerobic bacteria</p> Signup and view all the answers

    What is the mode of action of daptomycin?

    <p>Forming an ion-conducting channel in the bacterial cytoplasmic membrane</p> Signup and view all the answers

    What is the primary indication for the use of daptomycin?

    <p>Skin and soft tissue infections</p> Signup and view all the answers

    What is a common adverse effect of daptomycin?

    <p>Reversible myopathy</p> Signup and view all the answers

    Why is daptomycin not active against gram-negative bacteria?

    <p>It cannot penetrate the gram-negative outer membrane</p> Signup and view all the answers

    What is the structure of daptomycin?

    <p>A cyclic lipopeptide antibiotic</p> Signup and view all the answers

    What is the effect of daptomycin on bacterial membranes?

    <p>It forms an ion-conducting channel in the membrane</p> Signup and view all the answers

    What is the result of the insertion of the lipid portion of daptomycin into the bacterial cytoplasmic membrane?

    <p>Ions can escape from the bacterium</p> Signup and view all the answers

    What is the current status of an oral formulation of daptomycin?

    <p>It is not available</p> Signup and view all the answers

    What is the potential of daptomycin against aerobic gram-positive bacteria?

    <p>Excellent activity</p> Signup and view all the answers

    What type of infections is daptomycin currently effective against?

    <p>Skin and soft tissue infections</p> Signup and view all the answers

    What is the current status of daptomycin's effectiveness against other types of infections?

    <p>Under investigation</p> Signup and view all the answers

    What is depicted in Figure 5-20?

    <p>The structure of daptomycin</p> Signup and view all the answers

    What is the classification of daptomycin based on its activity?

    <p>A potent agent against aerobic gram-positive bacteria</p> Signup and view all the answers

    What is the current status of daptomycin's clinical trials?

    <p>Ongoing</p> Signup and view all the answers

    What is the potential benefit of daptomycin in the treatment of infections?

    <p>Effective treatment of skin and soft tissue infections</p> Signup and view all the answers

    Why did colistin fall into disfavor in the early 1980s?

    <p>Because of its perceived toxicities and the availability of safer alternatives</p> Signup and view all the answers

    What is the property of colistin that allows it to bind to lipopolysaccharide molecules in the bacterial outer membrane?

    <p>Its positive charge</p> Signup and view all the answers

    What is the function of the fatty acid side chain in colistin?

    <p>To facilitate insertion into the outer membrane</p> Signup and view all the answers

    What is the result of colistin's disruption of the normally tightly packed lipopolysaccharide molecules?

    <p>Increased permeability and lysis of the bacterium</p> Signup and view all the answers

    Which of the following bacteria is susceptible to colistin?

    <p>All of the above</p> Signup and view all the answers

    What is a mechanism of resistance to colistin?

    <p>Alteration of the negative charge associated with lipopolysaccharide</p> Signup and view all the answers

    What is the structure of colistin?

    <p>A cyclic decapeptide with a fatty acid side chain</p> Signup and view all the answers

    How does colistin disrupt the bacterial outer membrane?

    <p>By binding to lipopolysaccharide molecules</p> Signup and view all the answers

    What is the effect of colistin on the bacterial outer membrane?

    <p>Increased permeability and lysis of the bacterium</p> Signup and view all the answers

    What is the type of bacteria that colistin lacks activity against?

    <p>Gram-positive bacteria</p> Signup and view all the answers

    What is the primary toxicity associated with the use of colistin?

    <p>Nephrotoxicity</p> Signup and view all the answers

    What is the mechanism of action of colistin?

    <p>It binds to and disrupts the bacterial outer membrane</p> Signup and view all the answers

    What is the primary reason for the revival of colistin in the management of multidrug-resistant Gram-negative bacterial infections?

    <p>Its ability to overcome resistance to other antibiotics</p> Signup and view all the answers

    Which of the following bacteria is susceptible to colistin?

    <p>E. coli</p> Signup and view all the answers

    What is the result of the combination of properties of colistin?

    <p>It is useful in the treatment of infections caused by aerobic gram-negative bacteria</p> Signup and view all the answers

    What is the effect of colistin on the bacterial outer membrane?

    <p>It disrupts the bacterial outer membrane</p> Signup and view all the answers

    What is the common side effect of colistin?

    <p>Dizziness</p> Signup and view all the answers

    Study Notes

    Cephalosporins

    • 5% to 10% of individuals allergic to penicillin will also have a reaction to cephalosporins
    • Individuals with a history of severe immediate hypersensitivity reactions to penicillin should not be treated with cephalosporins
    • Rare adverse effects of cephalosporins include reversible neutropenia, thrombocytosis, hemolysis, diarrhea, and elevated liver function tests
    • Cefotetan can cause hypoprothrombinemia and a disulfram-like reaction when used with alcohol

    History of Cephalosporins

    • Cephalosporins were discovered by Italian scientist Giuseppe Brotzu in the 1940s
    • Brotzu identified the microbe Cephalosporium acremonium as producing a substance that inhibited bacterial growth
    • This substance became the backbone for synthesizing early cephalosporins

    Second-Generation Cephalosporins

    • True cephalosporins have activity equivalent to first-generation agents
    • Cefoxitin and cefotetan have little activity against gram-positive bacteria
    • Second-generation cephalosporins are effective against many strains of Staphylococcus aureus and some gram-negative bacteria, including E. coli, Klebsiella pneumoniae, Proteus mirabilis, and Haemophilus influenzae

    Limitations of Cephalosporins

    • First-generation cephalosporins cannot bind the PBPs of MRSA and MRSE or many highly penicillin-resistant Streptococcus pneumoniae
    • Most cephalosporins lack activity against L. monocytogenes and the enterococci
    • First-generation cephalosporins have limited activity against aerobic and facultative gram-negative bacteria, anaerobes, intracellular bacteria, and spirochetes

    Second-Generation Cephalosporins

    • Differ in their activity against aerobic gram-positive bacteria
    • True cephalosporins are active against aerobic gram-positive cocci, similar to first-generation agents
    • Cephamycins (cefotetan and cefoxitin) have limited activity against this group of bacteria
    • Strength of second-generation agents lies in their increased activity against aerobic and facultative gram-negative bacteria
    • More potent against E. coli, K. pneumoniae, and P. mirabilis than first-generation agents
    • Active against Neisseria spp. and H. influenzae (including β-lactamase-producing strains)

    Cephamycins

    • Have enhanced stability to the β-lactamases of some anaerobes, such as B. fragilis
    • Methoxy group on the β-lactam ring results in diminished activity against staphylococci and streptococci
    • Decreased affinity for the PBPs of these bacteria

    Carbapenems

    • Among the most broadly active antibiotics in use today
    • Often the last line of defense against many organisms that are resistant to other antimicrobial agents
    • Four members of this class are commercially available: imipenem, meropenem, doripenem, and ertapenem
    • Structure of carbapenems is related to that of penicillins and cephalosporins
    • Properties of carbapenems include:
      • Small size and charge characteristics that allow them to utilize special porins in the outer membrane of gram-negative bacteria
      • Resistance to cleavage by most β-lactamases
      • Affinity for a broad range of PBPs from many different kinds of bacteria

    Third-Generation Cephalosporins

    • Have moderate activity against aerobic gram-positive bacteria
    • Inhibit most strains of penicillin-susceptible S. pneumoniae
    • Active against the spirochete Borrelia burgdorferi
    • Little activity against anaerobic bacteria
    • Modification of the aminothiazolyl group at R1 results in:
      • Increased penetration of these agents through the bacterial outer membrane
      • Increased affinity for PBPs
      • Increased stability in the presence of some plasmid-encoded β-lactamases
    • Enhanced activity against E. coli, Klebsiella spp., Proteus spp., Neisseria spp., and H. influenzae relative to second-generation cephalosporins

    Carbapenems

    • Carbapenems are a class of antibiotics that are among the most broadly active antibiotics in use today.
    • They are often the last line of defense against many organisms that are resistant to other antimicrobial agents.
    • There are four commercially available carbapenems: imipenem, meropenem, doripenem, and ertapenem.

    Structure and Properties

    • Carbapenems have a β-lactam ring fused to a five-membered ring with variable side chains.
    • The five-membered ring differs from the thiazolidine ring of penicillin in two ways: a methylene group replaces sulfur, and the ring contains a double bond.
    • This structure results in three properties that account for their broad spectra of activity:
    • They are small and have charge characteristics that allow them to utilize special porins in the outer membrane of gram-negative bacteria to gain access to PBPs.
    • They are resistant to cleavage by most β-lactamases.
    • They have an affinity for a broad range of PBPs from many different kinds of bacteria.

    Ertapenem

    • Ertapenem differs from imipenem, meropenem, and doripenem in its R2 side chain, which accounts for its somewhat distinctive antimicrobial and pharmacologic properties.
    • Ertapenem is less active against aerobic gram-positive bacteria, P. aeruginosa, and Acinetobacter spp. than the other carbapenems.
    • Ertapenem compensates for this weakness by requiring only once per day dosing.

    Toxicity

    • Carbapenem use is associated with several adverse events, including nausea and vomiting, diarrhea, rash, and drug fever.
    • Seizures are a more worrisome complication associated with carbapenems, particularly in patients with preexisting central nervous system disease and renal insufficiency.

    Spectrum of Activity

    • Carbapenems have excellent activity against a broad spectrum of bacteria, including:
    • Most aerobic gram-positive bacteria
    • Most aerobic gram-negative bacteria
    • Most anaerobes
    • As a result, these compounds are among the most powerful antibacterial agents in use today.

    Resistance

    • Resistance to carbapenems occurs when bacteria overcome the advantageous aspects of these antibiotics.
    • Examples of resistance mechanisms include:
    • P. aeruginosa acquiring mutations that result in loss of production of the outer membrane porin used by carbapenems to gain access to the periplasm.
    • Enterococcus faecium and methicillin-resistant staphylococci producing altered PBPs that do not bind carbapenems.
    • Bacteria acquiring the ability to produce extremely powerful β-lactamases that are capable of cleaving carbapenems.

    Monobactams

    • Monobactams are bacterially derived antibiotics consisting of a lone β-lactam ring, unlike penicillins, cephalosporins, and carbapenems which have linked two-ring structures.
    • Aztreonam is a synthetic monobactam that combines useful features of other β-lactam antibiotics.

    Aztreonam Structure

    • Aztreonam has a β-lactam ring and an R1 side chain similar to ceftazidime.
    • The aminothiazolyl group in the side chain improves aerobic gram-negative coverage.

    Antimicrobial Activity of Monobactams

    • Aztreonam has excellent activity against:
      • Haemophilus influenzae
      • Neisseria spp.
      • Most Enterobacteriaceae
      • Many Pseudomonas aeruginosa
    • Aztreonam has intermediate activity against P. aeruginosa.
    • It does not bind to PBPs of gram-positive or anaerobic bacteria, making it ineffective against these organisms.

    Resistance to Aztreonam

    • Resistance occurs in some Enterobacteriaceae and P. aeruginosa due to:
      • Changes in outer membrane permeability
      • Destruction by β-lactamases

    Toxicity

    • Aztreonam is not associated with nephrotoxicity.
    • It is a renal-sparing alternative to aminoglycosides, with activity against aerobic gram-negative bacteria.
    • There are no allergic cross-reactions between aztreonam and other β-lactams, making it safe for patients with penicillin allergies.

    Summary

    • Aztreonam is the only commercially available monobactam.
    • It has excellent activity against aerobic gram-negative bacteria but is not effective against gram-positive or anaerobic bacteria.
    • It is a relatively safe drug and can be used in individuals with allergies to other β-lactam agents.

    Rifamycins

    • Rifampin binds to bacterial RNA polymerase and inhibits synthesis of RNA
    • Rifampin is used primarily in the treatment of diseases caused by Mycobacterium tuberculosis and Neisseria meningitidis
    • The rifamycins are usually used in conjunction with other antimicrobial agents because resistance to rifamycins develops during monotherapy

    Aminoglycosides

    • Aminoglycosides are among the oldest antibiotics, dating back to the purification of streptomycin from the bacterium Streptomyces griseus in 1944
    • Neomycin became available in 1949, followed by gentamicin in 1963, tobramycin in 1967, and amikacin in 1972
    • Aminoglycosides were initially active against both gram-negative and gram-positive bacteria

    Glycopeptides

    • Glycopeptide antibiotics are peptides with sugar moieties attached to them
    • Vancomycin and telavancin are two members of this group
    • Glycopeptides are poorly absorbed in the gastrointestinal tract, so they must be given intravenously to treat systemic infections
    • Their activity is restricted to gram-positive organisms due to their large size, which prevents them from passing through porins in the outer membranes of gram-negative bacteria
    • Vancomycin and telavancin are active against nearly all staphylococci and streptococci, including methicillin-resistant staphylococci and strains of penicillin-resistant S.pneumoniae
    • Susceptibility among enterococci is now variable

    Rifamycins

    • Rifampin binds to bacterial RNA polymerase and inhibits synthesis of RNA
    • Rifampin is used primarily in the treatment of diseases caused by Mycobacterium tuberculosis and Neisseria meningitidis
    • The rifamycins are usually used in conjunction with other antimicrobial agents because resistance to rifamycins develops during monotherapy

    Aminoglycosides

    • Aminoglycosides are among the oldest antibiotics, dating back to the purification of streptomycin from the bacterium Streptomyces griseus in 1944
    • Neomycin became available in 1949, followed by gentamicin in 1963, tobramycin in 1967, and amikacin in 1972
    • Aminoglycosides were initially active against both gram-negative and gram-positive bacteria

    Glycopeptides

    • Glycopeptide antibiotics are peptides with sugar moieties attached to them
    • Vancomycin and telavancin are two members of this group
    • Glycopeptides are poorly absorbed in the gastrointestinal tract, so they must be given intravenously to treat systemic infections
    • Their activity is restricted to gram-positive organisms due to their large size, which prevents them from passing through porins in the outer membranes of gram-negative bacteria
    • Vancomycin and telavancin are active against nearly all staphylococci and streptococci, including methicillin-resistant staphylococci and strains of penicillin-resistant S.pneumoniae
    • Susceptibility among enterococci is now variable

    Daptomycin Structure and Antimicrobial Activity

    • Daptomycin is a novel cyclic lipopeptide antibiotic approved for use in the United States in 2003.
    • The lipid portion of daptomycin inserts into the bacterial cytoplasmic membrane, forming an ion-conducting channel that allows ions to escape from the bacterium, resulting in bacterial death.
    • Daptomycin is active against many aerobic gram-positive bacteria, including:
      • Streptococcus pyogenes
      • Viridans group streptococci
      • Streptococcus pneumoniae
      • Staphylococci
      • Enterococci
    • Daptomycin is not active against gram-negative organisms because it cannot penetrate the gram-negative outer membrane to reach the cytoplasmic membrane.
    • Daptomycin has poor activity in the lungs and should not be used to treat pneumonia.

    Daptomycin Usage and Toxicity

    • Daptomycin has been primarily studied in the treatment of skin and soft tissue infections.
    • An oral formulation of daptomycin is not available.
    • Daptomycin is relatively well tolerated, but reversible myopathy has been observed at higher doses.
    • Other adverse effects include phlebitis, rash, and gastrointestinal adverse effects.

    Colistin

    • Colistin is an antibiotic that was first used in the 1950s, but fell out of favor in the early 1980s due to perceived toxicities and the availability of safer alternatives.
    • However, colistin has again become a popular choice for clinicians faced with few options in the treatment of multidrug-resistant gram-negative bacteria.

    Colistin

    • A cationic (positively charged) cyclic decapeptide with a fatty acid side chain, belonging to the polymyxin group of antibiotics.
    • Has activity against many aerobic gram-negative bacteria, including Pseudomonas aeruginosa, E. coli, and Klebsiella spp.
    • Effective against multidrug-resistant strains of these bacteria.
    • Lacks activity against other gram-negative bacteria (e.g., Proteus and Serratia spp.), gram-positive bacteria, and anaerobic bacteria.
    • Toxicity: associated with nephrotoxicity (decreased creatinine clearance) and neurotoxicity (e.g., dizziness, weakness, ataxia, paresthesias, vertigo).
    • Binds to and disrupts the bacterial outer membrane, leading to increased permeability and eventually, lysis of the bacterium.
    • Resistance occurs by altering the negative charge associated with lipopolysaccharide, decreasing the interaction between colistin and lipopolysaccharide.

    Mechanism of Action

    • The positive charge allows colistin to bind to the negatively charged lipopolysaccharide molecules in the bacterial outer membrane.
    • The fatty acid tail facilitates further insertion of colistin into the outer membrane.
    • Disrupts the normally tightly packed lipopolysaccharide molecules, leading to increased permeability and eventually, lysis of the bacterium.

    Daptomycin

    • Not discussed in detail, but mentioned as a separate antibiotic with a different mechanism of action and spectrum of activity.

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    This quiz covers the allergic reactions to penicillin and cephalosporins, including the risk of cross-reactivity and rare adverse effects.

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