Pharmacology: β-lactams and Cell Wall Synthesis Inhibitors
Terms in this set (93)
What is the mechanism of action of β-lactamases?
β-lactamases (penicillinases, cephalosporinases) are bacterial enzymes that hydrolyze the β-lactam ring of certain penicillins and cephalosporins, rendering them inactive.
What is the mechanism of action of all β-lactam antibiotics?
All β-lactams are
and act to
inhibit cell wall synthesis during bacterial growth, resulting in cell lysis
bind and inactivate penicillin binding proteins
* involved in the final stage of cell wall synthesis. It is during this stage that peptidoglycan chains of polysaccharides and polypeptides cross-link to form the cell wall. Autolytic enzymes of peptidoglycan are normally present in the bacterial cell wall but are strictly regulated to allow breakdown of the peptidoglycan only at growing points. β-lactam inhibition of cell wall synthesis leads to activation of the autolytic system, which initiates a cell death program.
What are three general mechanisms of bacterial resistance to the β-lactams?
1. Decreased penetration to the target site
2. Alteration of the target site
3. Inactivation by a bacterial enzyme
Why are Gram-negative bacteria more resistant to β-lactams?
To gain transmembrane entry and access to the PBPs, β-lactams must pass through hydrophilic porins (channels). A lack of these porins is a major factor in the resistance of some bacteria (Pseudomonas aeruginosa) to many β-lactam antibiotics. Gram-positive bacteria have a cell wall that is easily crossed by β-lactams and do not require the presence of these porins.
What is the cause of resistance to penicillin in pneumococci, methicillin in staphylococci and vancomycin in enterococci?
Alterations in PBPs influences their binding affinity for β-lactams and therefore affects the sensitivity of the altered bacterial cell to inhibition by these drugs.
Why are clavulanic acid, sulbactam, and tazobactam used in combination with penicillins?
These are β-lactamase inhibitors used in combination with penicillins to prevent their inactivation.
What is the drug of choice for syphilis?
is the drug of choice for syphilis (benzathine penicillin), in strep infections (especially to prevent rheumatic fever) and for susceptible pneumococci.
What is the drug if choice for streptococcal infections, especially to prevent rheumatic fever?
is the drug of choice for syphilis (benzathine penicillin), in strep infections (especially to prevent rheumatic fever) and for susceptible pneumococci.
Which organisms is penicillin G effective against?
1. Gram positive cocci (except β-lactamase-producing staphylococci, penicillin-resistant pneumococci, enterococci, and MRSA)
2. Gram-positive rods such as Listeria and C. perfringens
3. Gram-negative cocci such as Neisseria (except β-lactamase-producing Neisseria gonorrhea)
4. Most anaerobes (except bacteroides)
5. Certain spirochetes such as Treponema pallidum
Describe the spectrum of penicillin V. What kinds of infections is it used for?
Penicillin V has a similar antibacterial spectrum to Penicillin G. It is an oral drug used mainly for mild to moderate oropharyngeal infections.
What is the indicated treatment for "strep throat"?
Penicillin V is the drug of choice for the treatment of 'Strep throat'.
What is the spectrum for methicillin, nafcillin, oxacillin, and dicloxacillin?
These antistaphylococcal penicillins inhibit β-lactamase-producing staphylococci, but are inactive against MRSA. These penicillins have a very narrow spectrum and have less intrinsic activity than penicillin G for most bacteria and are ineffective for enterococci, Listeria, and Neisseria sp.
What is the primary indication for antistaphylococcal penicillins?
The primary use of the antistaphylococcal penicillins is in the treatment of known or suspected staphylococcal infections.
Describe the spectrum for amoxicillin and ampicillin.
In addition to
activity against Gram-positive bacteria
, these have
activity against Gram-negative bacilli
as they are able to penetrate the porin channels of the bacteria. They however, remain susceptible to β-lactamases. Their clinical use includes indications similar to penicillin G as well as infections resulting from E.coli, Proteus mirabilis, Salmonella, Shigella, enterococci, and H.influenzae, although resistant strains can occur. When used in combination with β-lactamase inhibitors (eg, clavulanic acid) their antibacterial activity is enhanced.
Which has a higher bioavailability, amoxicillin or ampicillin?
Amoxicillin and ampicillin have an identical spectrum of activity, but amoxicillin is better absorbed from the intestine when administered orally and yields higher blood and urine levels.
What are the uses of extended spectrum penicillins?
Amoxicillin is commonly prescribed for children and in pregnancy due to its extended spectrum and safety. Both drugs are commonly used in the
treatment of major upper respiratory bacterial infections caused by S. pneumoniae and H. influenzae.
They constitute effective therapy for acute otitis media, streptococcal pharyngitis, pneumonia, skin infections, UTI's etc. caused by sensitive strains of these organisms. In enterococci and listerial infections, ampicillin is synergistic with aminoglycosides.
What is the spectrum of antipseudomonal penicillins?
These drugs can penetrate the porin channel of Gram-negative bacteria in high doses and are more resistant to the β-lactamases of certain organisms, such as Pseudomonas aeruginosa, proteus and enterobacter species. They are most useful in infections caused by these organisms.
What is the primary use for carbenicillin, ticarcillin, and piperacillin?
All of the antipseudomonal penicillins are commonly
used to treat pseudomonas
, the choice of which is often solely based upon cost. They are also used in the treatment of moderate-severe infections of susceptible organisms (Gram-negatives suspected in uncomplicated and complicated skin, gynecologic and intra-abdominal infections).
Which antipseudomonal penicillin is strongest?
has superior activity against P. aeruginosa compared to carbenicillin and ticarcillin; however it is susceptible to some β-lactamases and is often used in combination with β-lactamase inhibitors to enhance its activity. Piperacillin also has activity against some strains of Klebsiella.
What is carbenicillin indanyl sodium indicated for?
Carbenicillin indanyl sodium is an orally absorbed form of carbenicillin which may be indicated for oral therapy of
resistant urinary tract infections
. Oral carbenicillin is not effective for therapy of infections outside of the urinary tract.
What are the uses of repository penicillins?
Common uses of the repository penicillins include the treatment of syphilis and rheumatic fever prophylaxis.
What are repository penicillins?
Penicillin G procaine and penicillin G benzathine were developed to prolong the duration of penicillin G. Both agents release penicillin G slowly from the area in which they are injected and produce relatively low but persistent concentrations of antibiotic in the blood. The long persistence of penicillin in the blood reduces cost, need for repeated injections, and local trauma. Both procaine and benzathine have local anesthetic effects and account for in part for the fact the injections are virtually painless.
Which penicillin is not suitable for oral absorption?
Gastrointestinal absorption of
is erratic, so it is not suitable for oral absorption.
Which penicillins are acid-stable and well absorbed in the stomach?
Dicloxacillin, ampicillin and amoxicillin are acid-stable and relatively well absorbed.
How does food affect oral absorption of penicillins?
Absorption of most oral penicillins (amoxicillin is an exception) is impaired by food, and the drugs should be administered at least 1-2 hours before or after a meal.
Describe the distribution of penicillins throughout the body.
All of the penicillins achieve therapeutic levels in pleural, pericardial, peritoneal and synovial fluids, as well as urine. Levels in bile, especially those of nafcillin, ampicillin, and piperacillin, are higher than corresponding serum levels. Penicillin levels in the prostate and eye are insufficient to be therapeutically effective. The penicillins penetrate the CSF poorly in the absence of inflammation but achieve therapeutic levels in patients with meningitis who are given high dose parenteral therapy.
How are most penicillins excreted?
Most, but not all, are excreted in urine and are dependent on kidney function.
Which penicillins are excreted independent of renal function and therefore not requiring dosage adjustment?
Nafcillin follows biliary excretion
oxacillin and dicloxacillin are eliminated by both
renal and biliary excretion. No dosage adjustment is required for these drugs in renal failure.
What is the most common adverse effect to penicillins? Why?
are the most common adverse effects. Penicilloic acid (breakdown product of penicillin) is the major antigenic determinant that causes allergic reactions with pruritus, flushing, urticaria, angioedema, wheezing, laryngeal edema, serum sickness-type reactions, hypotension, and/or anaphylaxis. A low incidence of cross-allergic reactions between β-lactam antibiotics do occur.
Which penicillins cause a maculopapular rash? Under what circumstances?
Amoxicillin and ampicillin
can both cause a maculopapular skin rash that is not due to an allergic reaction. This type of rash frequently
occurs when these drugs are inappropriately prescribed for a viral illness
, such as infectious mononucleosis.
What common gastrointestinal disturbance often follows treatment with ampicillin?
, related to overgrowth and production of a toxin by Clostridium difficile, has been associated with ampicillin treatment.
Which penicillins are more likely to cause diarrhea?
Diarrhea is a frequent nonspecific complication of antibiotic therapy, especially with oral antibiotics such as
ampicillin or amoxicillin
Which penicillin was discontinued due to allergic interstitial nephritis?
All penicillins have the potential to cause this effect.
is no longer used due to it causing this effect.
Which penicillin may inhibit platelet function?
may cause a bleeding diathesis by inhibition of platelet function and prolongation of the bleeding time.
What is the cause of penicillin neurotoxicity?
Penicillin neurotoxicity occurs with high-dose penicillin therapy, particularly if excretion is delayed by renal disease, or if preexisting neurologic disease is present (eg, epilepsy). High doses or intrathecal delivery of any of the β-lactam antibiotics (in particular the penicillins) can be irritating to neuronal tissue and may result in seizures.
Which penicillin causes neutropenia as an adverse effect?
Neutropenia is associated with use of
Which penicillin causes hepatitis as an adverse effect?
Hepatitis is associated with use of
What is the indicated treatment for infective endocarditis?
Penicillin in combination with an aminoglycoside (most commonly gentamicin)
is a recommended treatment for infective endocarditis; in practices vancomycin is often substituted for penicillin due to the risk of resistant strains.
Can penicillins and aminoglycosides be placed in the same IV infusion?
No! Penicillins and aminoglycosides must never be placed in the same infusion fluid as they form an inactive complex.
Describe the synergistic effect of penicillins and aminoglycosides.
Aminoglycosides exert their effects on aerobic Gram-negative bacteria whilst penicillins are predominantly active against Gram-positive bacteria. The aminoglycosides are protein synthesis inhibitors thus must cross the cell wall to have an effect. Penicillins are able to facilitate the movement of the aminoglycosides through the cell wall (by inhibiting its production) thus; in combination the drugs have a greater effect.
Name the β-lactamase inhibitors. What are they used for?
Clavulanic acid, sulbactam and tazobactam
are all β-lactamase inhibitors. Although they do not have significant antibacterial activity, inhibit many (but not all) bacterial β-lactamases and can protect hydrolysable penicillins from inactivation by these enzymes.
What is unique about 5th generation cephalosporins?
They are unique in that they are the only cephalosporins with activity against MRSA.
Which bacteria are cephalosporins pretty much useless against?
All cephalosporins are considered inactive against enterococci, listeria, legionella, chlamydia, mycoplasma and acinetobacter species.
What is the major use of cefazolin?
The major use of cefazolin is for
(due to its long half-life) in selected conditions.
Describe the antibiotic spectrum of first generation cephalosporins.
Cefazolin (parenteral) and cephalexin (oral) are active against
, including staphylococci and common streptococci. Many strains of E. coli, P. mirabilis, and Klebsiella are also sensitive.
When are first generation cephalosporins used?
They are good penicillin G substitutes and clinical uses include treatment of infections caused by sensitive bacteria. They are rarely the drug of choice for any infections but oral drugs may be used for the treatment of UTI's and for staphylococcal and streptococcal infections including cellulitis and soft tissue abscesses.
What are the clinical uses of second generation cephalosporins?
Examples of clinical uses include
sinus, ear, and respiratory infections caused by H. influenzae or M. catarrhalis (cefamandole, cefaclor)
and infections caused by the anaerobe
Bacteroides fragilis (cefotetan, cefoxitin)
. The combination of activity against common aerobic and facultative Gram-negative bacilli plus Bacteroides has led to the use of these drugs (cefotetan, cefoxitin) in the
prophylaxis and therapy of infections in the abdominal and pelvic cavities
Describe the antibiotic spectrum of 3rd generation cephalosporins.
These drugs have increased activity against Gram-negative organisms resistant to other β-lactam drugs and an ability to penetrate the BBB. They are highly active against Enterobacteriacae (E.coli, P.mirabilis), Neisseria, and H. influenzae. They are less active against most Gram-positive organisms than the first generation drugs and are inactive against enterococci, Listeria, MRSA, and Acinetobacter.
What is the drug of choice for penicillin-resistant gonorrhea and meningitis caused by ampicillin-resistant H. influenza?
is the drug of choice. It is also recommended for the treatment of Lyme disease involving the CNS or joints, and for the prophylaxis of meningitis in exposed individuals (including pregnant women).
Which 3rd generation cephalosporins have a better effect against P. aeruginosa?
Cefoperazone and ceftazidime
both have activity against P. aeruginosa.
Why do cefotetan, cefoperazone, and cefomandole cause bleeding?
Cefotetan, cefoperazone and cefomandole (2nd gen) contain an
N-methylthiotetrazole (NMTT) side chain
that can dissociate from the parent antibiotic in solution/vivo and competitively inhibit vitamin K action, leading to prolongation of the prothrombin time and bleeding. This side chain is also associated with a disulfiram-like reaction to alcohol.
What is cefepime?
Cefepime (parenteral administration only) is a 4th generation cephalosporin that is more resistant to β-lactamases produced by Gram-negative organisms (Enterobacter, Haemophilis, Neisseria) and some penicillin-resistant pneumococci. Cefepime combines the Gram-positive activity of 1st-generation agents with the wider Gram-negative spectrum of 3rd-generation drugs.
What is unique about ceftaroline?
Unlike other β-lactams, ceftaroline (parenteral administration only)
binds PBP2a, a penicillin binding protein encoded by MRSA.
What is ceftaroline used for?
Ceftaroline is useful in the
treatment of MRSA skin/soft tissue infection
, particularly if Gram-negative organisms are coinfecting.
Describe the spectrum of 5th generation cephalosporins.
The spectrum of activity for
approximates that of ceftriaxone; thus, it is inactive against P. aeruginosa, Acinetobacter spp, and B.fragilis.
Which cephalosporins are available orally?
Drugs available for oral use include: cephalexin, cefaclor, and cefixime.
Which cephalosporin readily crosses the BBB?
is well distributed and crosses the BBB easily, it is also highly protein bound.
How are cephalosporins excreted?
The major route of elimination is renal excretion. However, cefoperazone and ceftriaxone are excreted mainly in the bile.
Why is ceftriaxone contraindicated in pregnancy?
Ceftriaxone should not be used in pregnancy as it can cross the BBB and
displace bilirubin from binding sites leading to kernicterus
What are the adverse effects of cephalosporins?
2. Pain at IM injection sites
3. Phlebitis has been reported after IV administration.
What is the spectrum of activity for carbapenems?
The carbapenems (imipenem and meropenem) are synthetic β-lactam antibiotics which have low susceptibility to β-lactamases. They have a very broad spectrum of activity against Gram-positive cocci, Gram-negative rods, aerobes and anaerobes. They are effective against pseudomonas and are often used to treat this alongside an aminoglycoside.
True or false: carbapenems are useful against MRSA.
False: they are not effective against MRSA.
What is the drug of choice for enterobacter infections and extended-spectrum, β-lactamase producing Gram-negatives?
Carbapenem antibiotics are currently the drugs of choice.
Which organisms are developing carbapenemases?
Watch out for carbapenem-resistant enterobacteriaceae and carbapenem-resistant klebsiella.
Why is imipenem administered with cilastatin?
Imipenem is rapidly inactivated by renal dehydropeptidase I to form a potentially nephrotoxic metabolite. Administering it with cilastatin, an inhibitor of this enzyme, increases the plasma half-life of imipenem and inhibits the formation of this metabolite.
Does meropenem require cilastatin?
Meropenem is not metabolized by renal dehydropeptidases and does not have to be given with cilastatin.
What are the adverse effects of imipenem?
It can cause GI distress (nausea, vomiting, diarrhea) and at very high levels CNS toxicity (provoking seizures).
What are the adverse effects of meropenem?
Meropenem is similar to imipenem (GI problems) apart from that it is less likely to cause seizures.
True or false: carbapenems have partial cross-allergenicity with penicillins.
True: the carbapenems have partial cross-allergenicity with penicillins.
What are the adverse effects of aztreonam?
Occasional skin rashes and elevation of serum aminotransferases, along with thrombophlebitis and pain at the injection site have been reported. When administered by the inhalation route the most common adverse effect is cough.
What is the spectrum of activity for aztreonam?
The monobactams (aztreonam) have a spectrum of activity
limited to aerobic Gram-negative rods (including pseudomonas)
. In contrast to other β-lactam drugs they do not have any activity against Gram-positive bacteria or anaerobes. Aztreonam is resistant to the action of most β-lactamases.
What are the main uses of aztreonam?
The main uses of aztreonam include the treatment of urinary tract infections, lower respiratory tract infections, septicemia, skin/structure infections, intra-abdominal infections, and gynecological infections caused by susceptible
aerobic Gram-negative bacilli
What is the mechanism of action for vancomycin?
Vancomycin inhibits cell wall synthesis by
binding firmly to the D-Ala-D-Ala
terminus of nascent peptidoglycan pentapeptide. This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking. Both peptidoglycan polymerization and cell wall synthesis are inhibited and the cell becomes susceptible to lysis.
What is the most common cause of vancomycin resistance?
Resistance to vancomycin in enterococci is due to modification of the D-Ala-D-Ala binding site. The terminal D-Ala is replaced by D-lactate resulting in vancomycin being unable to bind to its target.
Describe the spectrum of activity for vancomycin.
bactericidal against Gram-positive bacteria only
, including staphylococci, MRSA, enterococci and PRSP. Vancomycin
with aminoglycosides is the first-line therapy for E. faecium and E. faecalis enterococcal endocarditis.
What is the first-line therapy for enterococcal endocarditis?
Use vancomycin with an aminoglycoside together.
What are the main uses of vancomycin?
The main uses of vancomycin are the treatment of
serious infections caused by β-lactam resistant Gram-positive
organisms. It is also used for the treatment of infections caused by Gram-positive organisms in individuals who have serious
allergies to β-lactam agents
. Vancomycin can be administered orally for the treatment of staphylococcal enterocolitis or antibiotic-associated
s* produced by C. difficile.
What are the adverse effects of vancomycin?
1. Phlebitis at injection site along with fever and chills.
2. 'Red-man' or 'red-neck' syndrome
3. Ototoxicity and nephrotoxicity (rare, in renal failure) are enhanced by amino glycosides coadministration.
What is "red-man" or "red-neck" syndrome?
After vancomycin, it's an infusion related flushing of the face and upper torso occurs relatively commonly, caused by the release of histamine. It can be prevented by prolonging the infusion time.
What is the mechanism of action for daptomycin?
It is known to bind to the cell membrane of sensitive bacteria via calcium-dependent insertion of its lipid tail. This results in depolarization of the cell membrane with potassium efflux and rapid cell death.
Describe the spectrum of activity for daptomycin.
Daptomycin has a similar spectrum of activity to vancomycin except that it is active against vancomycin-resistant strains of enterococci and S. aureus. It is inactive against Gram-negative bacteria.
What are the clinical uses of daptomycin?
Daptomycin is mainly used for the treatment of
complicated skin infections by susceptible aerobic Gram-positive organisms, S.aureus bacteremia (including right-sided native valve infective endocarditis caused by MSSA or MRSA), and severe infections caused by MRSA or VRE.
Its use is therefore restricted to these serious multi-drug resistant infections to prevent the development of resistance.
What are the adverse effects of daptomycin?
Adverse effects include constipation, nausea, headache and insomnia. Daptomycin can cause
myopathy and creatine phosphokinase levels should be monitored
What is the clinical use of bacitracin? Why?
Bacitracin is highly nephrotoxic when administered systemically and is used only topically for the treatment of mixed bacterial infections of the skin, wounds, or on mucus membranes.
What is the mechanism of action of bacitracin?
Bacitracin is a peptide antibiotic with activity against Gram-positive microorganisms. It inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall. Due to this unique mechanism, there is no cross-resistance between bacitracin and other antimicrobial drugs.
What is the mechanism of action of fosfomycin?
Fosfomycin is active against both Gram-positive and Gram-negative organisms. It inhibits the cytoplasmic enzyme
which is important in the early stages of cell wall synthesis.
What is the clinical use of fosfomycin?
Fosfomycin can be given only orally in the US and is approved for the treatment of
uncomplicated lower urinary tract infections.
Name the anti-staphylococcal penicillins.
Name the extended spectrum penicillins.
They're amoxicillin and ampicillin.
Name the anti-pseudomonal penicillins.
What are the first generation cephalosporins.
Name the 2nd generation cephalosporins.
Name the 3rd generation cephalosporins.