Pharmacology: Bacterial Protein Synthesis Inhibitors
Terms in this set (81)
Why don't protein synthesis inhibitors affect mammalian cells?
Bacteria have 70S ribosomes, whereas mammalian cells have 80S ribosomes. This difference forms the basis for the selective toxicity of these drugs against microorganisms without causing major effects on protein synthesis in mammalian cells. However, the bacterial ribosome does closely resemble the mammalian mitochondrial ribosome and some observed adverse effects are due to this structural similarity.
What is the mechanism of action of tetracyclines?
The tetracyclines enter microorganisms in part via passive diffusion and in part via an energy-dependent transport that is unique to the bacterial inner cytoplasmic membrane. Susceptible cells concentrate the drug intracellularly. Once inside the cell,
tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome, preventing binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex.
This prevents addition of amino acids to the growing peptide.
What are the three sources of tetracycline resistance?
1. Impaired influx/increased efflux by active transport
2. Proteins that interfere with binding to the ribosome
3. Enzymatic inactivation.
Describe the spectrum of activity for tetracyclines.
The tetracyclines are broad-spectrum, bacteriostatic drugs. They are active against many aerobic and anaerobic Gram-positive and Gram-negative bacteria.
What are the clinical uses of tetracyclines?
1. Infections of the respiratory tract, sinuses, middle ear, urinary tract and intestines.
Treatment of severe acne and rosacea.
Drugs of choice for Chlamydia, Mycoplasma pneumoniae, Lyme disease, Cholera, Anthrax (prophylaxis) and Rickettsia (Rocky Mountain spotted fever, typhus).
4. Syphilis in patients who are allergic to penicillin.
5. Combination regimens used for duodenal ulcer disease caused by H.pylori, in the prophylaxis and treatment of malaria, and in the treatment of plague, tularemia, and brucellosis.
What factors impair oral absorption of tetracyclines?
Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline). Absorption of all oral tetracyclines is impaired by multivalent cations (Ca2+, Mg2+, Fe2+) or by dairy products and antacids that contain multivalent cations.
Which tetracycline is useful for the meningococcal carrier state?
reaches very high concentration in tears and saliva, which makes it useful for the eradication of the meningococcal carrier state.
How are tetracyclines excreted?
Doxycycline is excreted mainly in the feces; the other drugs are eliminated primarily in the urine.
What are the adverse effects of tetracyclines?
1. Nausea, vomiting and diarrhea (direct GIT irritation)
Discoloration/hyperplasia of teeth and stunted growth
6. Vertigo and dizziness
Why are tetracyclines avoided during pregnancy and in children younger than 8 years old?
Tetracyclines are readily bound to calcium deposited in newly formed bone and teeth in young children. When given in pregnancy,
tetracyclines may be deposited in the fetal teeth leading to discoloration and in bone, where it may cause deformity and growth inhibition.
Because of these effects tetracyclines are FDA pregnancy category D and are generally avoided in pregnancy and children less than 8 years. They also cause hepatotoxicity in pregnancy.
Which tetracyclines cause vertigo?
Doxycyline and minocycline
concentrate in the endolymph of the ear leading to function being affected. (The "Dizzy" Doggy Cycling)
What is the mechanism of action for tigecycline?
The glycylcyclines (tigecycline) are a new class of antibiotics derived from tetracyclines, thus have a similar mechanism of action; they bind to the 30s bacterial ribosome but five times more tightly than the tetracyclines.
Are many bacteria resistant to tigecycline?
Tigecycline was specifically designed to overcome two common mechanisms of resistance, namely resistance mediated by acquired efflux pumps, and /or ribosomal protection. At present there has been little resistance reported for tigecycline. Proteus and P.aeruginosa however, are intrinsically resistant.
What is tigecycline used for?
Tigecycline has a very broad spectrum including activity against
MRSA, VISA and VRE
. Its major recommended use is for the
treatment of complicated skin, soft tissue and intra-abdominal infections
. It is also licensed for use in community-acquired pneumonia.
Your patient is in renal failure. Should you increase the dosage of tigecycline?
Elimination is primarily biliary
, and no dosage adjustment is needed for patients with renal insufficiency.
What are the adverse effects of tigecycline?
Tigecycline is subject to the same adverse effects as all the tetracyclines and is thus also contraindicated in pregnancy and young children. In addition to these effects, the
most common adverse effect of tigecycline is nausea and vomiting.
What is the mechanism of action of aminoglycosides?
The aminoglycosides act by irreversibly inhibiting protein synthesis. The drugs initially cross the outer membrane of the bacteria via passive diffusion before being actively transported across the cell membrane into the cytoplasm by an oxygen-dependent process. Once across the cell membrane, the aminoglycosides
bind to the 30S subunit prior to ribosome formation leading to misreading of the genetic code and inhibition of translocation. Elongation fails to occur and cell lysis normally occurs.
Which factors can inhibit aminoglycosides crossing through the outer membrane of bacteria?
This step can be inhibited in vitro by divalent cations, increased osmolality, acidic pH, and an anaerobic environment.
How does resistance to aminoglycosides occur?
1. Plasmid-associated enzymes that modify and inactivate the drugs by phosphorylation, adenylylation, and acetylation;
2. Receptor protein on the 30S ribosomal subunit may be deleted or altered due to mutation
3. Decreased accumulation (low influx, high efflux).
What is the post-antibiotic effect of aminoglycosides?
The PAE refers to the persistent suppression of bacterial growth that occurs after the drug has been removed. The PAE due to aminoglycosides is thought to be due to the drugs strong irreversible binding of the 30S ribosome.
What is meant by concentration-dependent killing of aminoglycosides?
Concentration-dependent killing refers to the ability of higher concentrations of aminoglycosides to induce more rapid, and complete killing of the microorganism. Due to this property aminoglycosides have greater efficacy when given as a single large dose than as multiple small doses. This is in contrast to the time-dependent killing of drugs such as the penicillins when in vivo efficacy is directly related to time above MIC and becomes independent of concentration once the MIC has been reached.
Which organisms are killed by aminoglycosides?
most active against aerobic Gram-negative
bacteria, sometimes MRSA in vitro (not adequate monotherapy), and Streptococcus and Staphylococcus when used in combination with cell wall inhibitors.
Which aminoglycoside is used to treat hepatic encephalopathy?
(little is absorbed from GI tract) is used in the treatment of hepatic encephalopathy.
What is the first-line treatment of hepatic encephalopathy?
Lactulose is commonly used as a first line treatment. By acidifying the gut lumen, lactulose traps NH4+ in the colon, effectively reducing plasma ammonia concentrations. Other important properties of lactulose include its prebiotic effect and its role as an osmotically active laxative. Neomycin is a second-line treatment due to the risk of serious side-effects.
Which aminoglycoside is used to treat plague?
Streptomycin is currently the most successful drug at treating plague (Yersinia Pestis).
Which aminoglycoside is great for treating infective endocarditis?
Gentamicin plus either a penicillin or (more commonly) vancomycin is the drug combination of choice in the empiric treatment of infective endocarditis.
What are the most frequent clinical uses of aminoglycosides?
The most frequent clinical uses of aminoglycosides (most commonly in combination with other drugs) is empiric therapy of serious infections, such as septicemia, nosocomial respiratory tract infections (Pseudomonas), complicated urinary tract infections, complicated intraabdominal infections, endocarditis and osteomyelitis caused by aerobic Gram-negative bacilli.
Describe the pharmacokinetics of aminoglycosides.
Aminoglycosides are dosed once-daily. They are not absorbed after oral administration and are thus administered parenterally (excluding neomycin which is a topical agent). They are well distributed but show poor penetration into the CSF, biliary tree, and bronchial secretions. Approximately 99% of the dose is eliminated unchanged in the urine and doses must be reduced in patients with renal insufficiency.
What are the primary adverse effects of aminoglycosides?
The primary toxicities of aminoglycosides are nephrotoxicity, ototoxicity, and rarely neuromuscular blockade.
Which aminoglycosides are more likely to cause nephrotoxicity?
Nephrotoxicity is more likely to be encountered when therapy is continued for more than five days, at higher doses and in patients with renal insufficiency. In addition, concurrent use with other nephrotoxic agents can potentiate the effect.
Neomycin (a reason why it is only used topically), tobramycin, and gentamicin
are the most nephrotoxic agents and result in rising serum creatinine levels or reduced creatinine clearance.
Which aminoglycosides are more likely to cause ototoxicity?
Neomycin (a reason why it is mostly used topically), kanamycin and amikacin
are the most ototoxic agents. Ototoxicity may be increased by the use of loop diuretics. Because ototoxicity has been reported after fetal exposure, the aminoglycosides are contraindicated in pregnancy unless the benefits outweigh the risks.
What are the absolute contraindications of aminoglycosides?
Myasthenia gravis and pregnancy are absolute contraindications to aminoglycoside use.
What is the mechanism of action of macrolides?
The macrolides (erythromycin, clarithromycin, azithromycin and telithromycin) are all structurally related bacteriostatic agents. They
bind to the 50S subunit of bacterial ribosomes, leading to inhibition of transpeptidation, translocation, chain elongation and ultimately protein synthesis.
How does resistance to macrolides arise?
1. Reduced membrane permeability or active efflux
2. Production of an esterase that hydrolyzes the drugs
3. Modification of the ribosomal binding site, either by chromosomal mutation or by a methylase.
Is there cross-resistance between macrolides?
between erythromycin, azithromycin, and clarithromycin for Gram-positive organisms by the alteration in ribosomal RNA mechanism. In contrast, resistance to telithromycin by this mechanism is as yet uncommon.
Which organisms are macrolides effective against?
The macrolides are mainly active against Gram-positive organisms with activity against some Gram-negative organisms. Azithromycin, clarithromycin and telithromycin have a broader spectrum of activity than erythromycin. Erythromycin is not active against S. aureus for example.
What are macrolides used for?
The greatest use of the macrolides is in the treatment
upper respiratory tract and soft-tissue infections
(eg, infections caused by H.influenzae, S.pneumoniae, Staphylococci, enterococci).
Erythromycin is also the current drug of choice for the treatment of Whooping cough (B.pertussis).
Macrolides have also been shown to have activity against Legionella,
, mycobacteria, rickettsia and Chlamydia.
Which macrolide is safest for pregnancy?
Erythromycin should be considered the safest macrolide in pregnancy, because of the years of clinical experience.
Which macrolide has the fewest drug interactions?
In contrast to the other macrolides, azithromycin does not appear to affect CYP enzymes and thus drug interactions are uncommon.
Which drugs are affected by macrolides?
Anticoagulants, carbamazepine, and theophylline are good examples. For the same reason, the combination of macrolides and statins is also not advised due to reports of increasing levels of myopathy. Erythromycin is also able to increase the plasma levels of digoxin by increasing its bioavailability.
What are the adverse effects of telithromycin?
It causes potentially fatal
hepatotoxicity, potentially fatal exacerbations of myasthenia gravis, and visual disturbances
. It should NOT be used for minor illnesses like sinusitis or bronchitis. Telithromycin is contraindicated in patients with myasthenia gravis.
What GIT problems can macrolides cause?
Nausea, diarrhea, abdominal pain are relatively common and occur via stimulation of motilin receptors.
Which macrolides cause hepatic abnormalities?
azithromycin and erythromycin
have been associated with hepatic abnormalities such as hepatitis cholestatic jaundice, hepatic necrosis and hepatic failure.
Which macrolides are associated with long QT syndrome?
Azithromycin, erythromycin, clarithromycin and telithromycin have all been associated with QT interval prolongation that can lead to Torsade de Pointes.
What rare complications can arise from macrolide use?
Severe reactions include anaphylaxis, Stevens-Johnson syndrome, and pseudomembranous colitis.
Name the common macrolides.
Name the common aminoglycosides.
What is the common glycylcycline?
What are the common tetracyclines?
What are the adverse effects of chloramphenicol?
1. Nausea, vomiting and diarrhea can occur.
2. Bone marrow depression (reversible RBC suppression)
3. Gray baby syndrome (cyanosis)
What is Gray Baby Syndrome?
Newborn infants lack an effective glucuronic acid conjugation mechanism required for the degradation of chloramphenicol. Consequently, the drug may accumulate, resulting in the Gray baby syndrome (vomiting, flaccidity, hypothermia, gray color, shock and collapse).
How does chloramphenicol affect other drugs?
Chloamphenicol inhibits CYP2C9 and 3A4, leading to increased serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin. Like other bacteriostatic drugs, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides.
Describe the spectrum of activity for chloramphenicol.
Chloramphenicol is a
broad-spectrum drug that is active against both aerobic and anaerobic Gram-positive and Gram-negative organisms.
What is chloramphenicol used for?
Chloramphenicol is used for the
treatment of serious infections resistant to other less toxic drugs
, or when its penetrability to the site of infection is clinically superior to other drugs to which the organism is susceptible; it is useful in infections caused by Bacteroides, H. influenzae, N. menigitidis, Salmonella and rickettsia. It is also known to be active against many vancomycin-resistant enterococci. One of the more common uses of chloramphenicol is in the topical treatment (no systemic adverse effects) of ear and eye infections, due to its broad spectrum and penetration of ocular tissues and the aqueous humor. However,
in the US this use is declining due to the associated risk of aplastic anemia even when the drug is given topically.
How does resistance to chloramphenicol occur?
Clinically significant resistance is due to either the
production of chloramphenicol acetyltransferase
, a plasmid-encoded enzyme that inactivates the drug, or
changes in membrane permeability
What is the mechanism of action for chloramphenicol?
Chloramphenicol enters cells via an active transport and
binds reversibly to the 50S subunit of the bacterial ribosome, inhibiting the peptidyl transferase step of protein synthesis.
It can also inhibit protein synthesis in mammalian mitochondrial ribosomes which can lead to bone marrow toxicity.
What are the adverse effects of clindamycin?
1. Diarrhea, nausea, and skin rashes.
2. Pseudomembranous colitis (high risk C. difficile)
3. Impaired liver function and neutropenia
Describe the spectrum of activity for clindamycin.
with activity against
bacteria including bacteroides.
What are the uses of clindamycin?
It is indicated for the treatment of
skin and soft tissue infections by streptococci, staphylococci, and some MRSA infections
. It is also used for the treatment of anaerobic
infections caused by bacteroides
and other anaerobes that participate in mixed infections. In combination with an aminoglycoside or cephalosporin, it's used to treat penetrating wounds of the gut and abdomen. In
combination with primaquine, it's an effective alternative to cotrimoxazole for moderate to moderately severe Pneumocystis jiroveci pneumonia (PCP) in AIDS patients
. It is also used in combination with pyrimethamine for AIDS related toxoplasmosis of the brain. Clindamycin is used as prophylaxis of endocarditis in valvular disease patients who are undergoing dental procedures and who are allergic to penicillin.
What is the mechanism of action for clindamycin? How does resistance occur?
Clindamycin inhibits protein synthesis by
binding to the 50S subunit of the bacterial ribosome
(like macrolides). Resistance to clindamycin thus generally confers cross-resistance to macrolides and is mainly due to either mutation of the ribosomal receptor site, modification of the receptor by a constitutively expressed methylase, or enzymatic inactivation of the drug. Gram- negative aerobic organisms and enterococci are intrinsically resistant to clindamycin due to poor permeability of the outer membrane.
What is the mechanism of resistance for streptogramins?
Resistance is uncommon but due to modification of the quinupristin binding site, enzymatic inactivation of dalfopristin, or increased efflux of the drugs.
Name the streptogramins.
Those are quinupristin and dalfopristin.
What is the mechanism of action for streptogramins?
Quinupristin-dalfopristin is a combination of two streptogramins in a 30:70 ratio. They act to inhibit bacterial protein synthesis synergistically by binding to separate sites on the 50S ribosome.
What are streptogramins used to kill?
The streptogramins are
bactericidal for most organisms except Enterococcus faecium
, which is killed slowly. They are active against Gram-positive cocci, including multidrug- resistant strains of streptococci, penicillin-resistant strains of S.pneumoniae, MRSA, and E.faecium.
What are streptogramins used for?
Due to their effectiveness at treating multi-drug resistant organisms, their
use is restricted to the treatment of infections caused by staphylococci or by vancomycin-resistant strains of E. faecium, but not E. faecalis
(which is intrinsically resistant).
What are the adverse effects of streptogramins?
The principal adverse effects are
infusion-related events, such as pain at the infusion site, and an arthalgia-myalgia syndrome
. GI effects (nausea, vomiting, diarrhea) and CNS effects (headache, pain) are also reported.
What is the mechanism of action for linezolid?
Linezolid inhibits protein synthesis by
preventing formation of the ribosome complex that initiates protein synthesis. It has a unique binding site, located on 23S ribosomal RNA of the 50S subunit.
This unique site results in no cross-resistance with other drug classes.
How does linezolid resistance develop?
Resistance to linezolid is caused by mutation of the binding site.
What is linezolid used for?
It is recommended for use against
vancomycin-resistant Enterococcus faecium (VRE) infections, nocosomial pneumonia caused by staphylococci (including MRSA) or Streptococcus pneumoniae, complicated and uncomplicated skin and skin structure infections and community-acquired pneumonia caused by susceptible Gram-positive infections
. Due to its ability to treat multi-drug resistant infections, the use of linezolid is mainly restricted to this role.
Which bacteria are affected by linezolid?
Linezolid is a
drug with activity against
organisms including staphylococci, streptococci, enterococci, Gram-positive anaerobic cocci, and Gram-positive rods such as Corynebacteria and Listeria monocytogenes. It also has activity against Mycobacterium tuberculosis.
Describe the pharmacokinetics of linezolid?
Linezolid is 100% bioavailable after oral administration and is also available for IV use. It has
no effect on CYP P450 enzymes, but is a weak, reversible inhibitor of MAO
. It therefore has the potential to interact with adrenergic and serotonergic drugs.
What are the adverse effects of long-term linezolid administration?
Long-term administration can result in
reversible myelosuppression, optic and peripheral neuropathy, and lactic acidosis.
These effects appear to occur more commonly in immunocompromised patients.
What are the short-term adverse effects of linezolid?
1. GI disturbances, headaches and rash.
2. Inhibition of MAO
What is the mechanism of action for fidaxomicin?
Fidaxomicin is a narrow-spectrum, macrocyclic antibiotic that inhibits bacterial protein synthesis by
binding to the sigma subunit of RNA polymerase
, resulting in inhibition of the enzyme.
What is the spectrum of activity for fidaxomicin.
Fidaxomicin is active against
Gram-positive aerobes and anaerobes
but lacks activity against Gram-negative bacteria. It is
especially active against Clostridium difficile.
What is fidaxomicin used for?
Fidaxomicin has been approved by the FDA for the
treatment of C.difficile colitis in adults.
Preliminary data have demonstrated it is as effective as oral vancomycin and may be associated with lower rates of relapsing disease. Unfortunately, it is considerably more expensive than vancomycin.
Why is fidaxomicin great for C. dificile treatment?
When fidaxomicin is administered orally, systemic absorptions is negligible but fecal concentrations are high. These properties make fidaxomicin ideal for treating C. difficile colitis whilst minimizing systemic effects of the drug (similar to vancomycin).
What are the adverse effects of fidaxomicin?
Fidaxomicin due to the lack of systemic effects appears to be well tolerated. Most reports of adverse effects appear to be gastrointestinal complaints.
What is the mechanism of action for mupirocin?
Mupirocin is a naturally occurring antibiotic active against most Gram-positive cocci, including methicillin-sensitive and methicillin-resistant S. aureus and most streptococci (but not enterococci). It works by
binding to bacterial isoleucyl transfer-RNA synthetase
resulting in the inhibition of protein synthesis.
What is mupirocin used for?
Mupirocin is active against most Gram-positive cocci, including MSSA and MRSA. Mupirocin has been approved to be used
via the intranasal route for the eradication of nasal colonization with MRSA in adult patients and healthcare workers
. It can also be used topically for the
treatment of impetigo
or secondary infected traumatic skin lesions due to S.aureus or S.pyogenes.
What are the adverse effects of mupirocin?
Mupirocin is generally well tolerated. Reports of adverse effects mainly include local or dermatologic effects eg,
burning, edema, tenderness, dry skin and pruritus
. High rates of mupirocin resistance have been observed when it is used long-term over months.