Protein Synthesis Inhibitors.pdf

Pharmacology Chemotherapy Protein Synthesis Inhibitors Protein Synthesis Inhibitors Content: Tetracyclines ……………………………………………………..… 6 Glycylcyclines ……………………………………………………..… 25 Aminoglycosides ……………………………………………………..… 32 Macrolides and Ketolides ……………………………………………………..… 49 Fidaxomicin ………………………………………………...

Pharmacology Chemotherapy Protein Synthesis Inhibitors Protein Synthesis Inhibitors Content: Tetracyclines ……………………………………………………..… 6 Glycylcyclines ……………………………………………………..… 25 Aminoglycosides ……………………………………………………..… 32 Macrolides and Ketolides ……………………………………………………..… 49 Fidaxomicin ……………………………………………………..… 70 Chloramphenicol ……………………………………………………..… 74 Clindamycin ……………………………………………………..… 83 Quinupristin/Dalfopristin ……………………………………………………..… 88 Oxazolidinones ……………………………………………………..… 95 Protein Synthesis Inhibitors Overview: A number of antibiotics exert their antimicrobial effects by targeting bacterial ribosomes and inhibiting bacterial protein synthesis. Most of these agents exhibit bacteriostatic activity. Bacterial ribosomes differ structurally from mammalian cytoplasmic ribosomes and are composed of 30S and 50S subunits (mammalian ribosomes have 40S and 60S subunits). In general, selectivity for bacterial ribosomes minimizes potential adverse consequences encountered with the disruption of protein synthesis in mammalian host cells. Protein Synthesis Inhibitors Overview: However, high concentrations of drugs such as chloramphenicol or the tetracyclines may cause toxic effects as a result of interaction with mitochondrial mammalian ribosomes, because the structure of mitochondrial ribosomes more closely resembles bacterial ribosomes. Figure 1 summarizes the antimicrobial protein synthesis inhibitors discussed in this chapter. Protein Synthesis Inhibitors Figure 1 – Summary of protein synthesis inhibitors. Tetracyclines Protein Synthesis Inhibitors Tetracyclines: Tetracyclines consist of four fused rings with a system of conjugated double bonds. Substitutions on these rings alter the individual pharmacokinetics and spectrum of antimicrobial activity. Tetracyclines Mechanism of Action: Tetracyclines enter susceptible organisms via passive diffusion and by an energydependent transport protein mechanism unique to the bacterial inner cytoplasmic membrane. Tetracyclines concentrate intracellularly in susceptible organisms. The drugs bind reversibly to the 30S subunit of the bacterial ribosome. This action prevents binding of tRNA to the mRNA–ribosome complex, thereby inhibiting bacterial protein synthesis (Figure 2). Tetracyclines Figure 2 – Mechanisms of action of the various protein synthesis inhibitors. aa = amino acid. Tetracyclines Antibacterial Spectrum: The tetracyclines are bacteriostatic antibiotics effective against a wide variety of organisms, including gram-positive and gram-negative bacteria, protozoa, spirochetes, mycobacteria, and atypical species. They are commonly used in the treatment of acne and Chlamydia infections (Figure 3). Tetracyclines Figure 3 – Typical therapeutic applications of tetracyclines. *A tetracycline + gentamicin. Tetracyclines Resistance: The most commonly encountered naturally occurring resistance to tetracyclines is an efflux pump that expels drug out of the cell, thus preventing intracellular accumulation. Other mechanisms of bacterial resistance to tetracyclines include enzymatic inactivation of the drug and production of bacterial proteins that prevent tetracyclines from binding to the ribosome. Resistance to one tetracycline does not confer universal resistance to all tetracyclines, and the development of cross-resistance may be dependent on the mechanism of resistance. Tetracyclines Pharmacokinetics: 1. Absorption: Tetracyclines are adequately absorbed after oral ingestion (Figure 4). Administration with dairy products or other substances that contain divalent and trivalent cations (for example, magnesium, calcium and aluminum antacids, or iron supplements) decreases absorption, particularly for tetracycline, due to the formation of nonabsorbable chelates (Figure 30.5). Both doxycycline and minocycline are available as oral and intravenous (IV) preparations. Tetracyclines Figure 4 – Administration and fate of tetracyclines. CSF = cerebrospinal fluid. Tetracyclines Figure 5 – Effect of antacids and milk on the absorption of tetracyclines. Tetracyclines Pharmacokinetics: 2. Distribution: The tetracyclines concentrate well in the bile, liver, kidney, gingival fluid, and skin. Moreover, they bind to tissues undergoing calcification (for example, teeth and bones) or to tumors that have high calcium content. Penetration into most body fluids is adequate. Only minocycline and doxycycline achieve therapeutic levels in the cerebrospinal fluid (CSF). Minocycline also achieves high concentrations in saliva and tears, rendering it useful in eradicating the meningococcal carrier state. Tetracyclines Pharmacokinetics: 2. Distribution: All tetracyclines cross the placental barrier and concentrate in fetal bones and dentition. 3. Elimination: Tetracycline is primarily eliminated unchanged in the urine, whereas minocycline undergoes hepatic metabolism and is eliminated to a lesser extent via the kidney. Doxycycline is preferred in patients with renal dysfunction, as it is primarily eliminated via the bile into the feces. Tetracyclines Adverse Effects: 1. Gastric Discomfort: Epigastric distress commonly results from irritation of the gastric mucosa (Figure 6) and is often responsible for noncompliance with tetracyclines. Esophagitis may be minimized through coadministration with food (other than dairy products) or fluids and the use of capsules rather than tablets. Note: Tetracycline should be taken on an empty stomach. Tetracyclines Figure 6 – Some adverse effects of tetracyclines. GI = gastrointestinal. Tetracyclines Adverse Effects: 2. Effects on Calcified Tissues: Deposition in the bone and primary dentition occurs during the calcification process in growing children. This may cause discoloration and hypoplasia of teeth and a temporary stunting of growth. For this reason, the use of tetracyclines is limited in pediatrics. Tetracyclines Tetracyclines Adverse Effects: 3. Hepatotoxicity: Rarely hepatotoxicity may occur with high doses, particularly in pregnant women and those with preexisting hepatic dysfunction or renal impairment. 4. Phototoxicity: Severe sunburn may occur in patients receiving a tetracycline who are exposed to sun or ultraviolet rays. This toxicity is encountered with any tetracycline, but more frequently with tetracycline and demeclocycline. Patients should be advised to wear adequate sun protection. Tetracyclines Adverse Effects: 5. Vestibular Dysfunction: Dizziness, vertigo, and tinnitus may occur particularly with minocycline, which concentrates in the endolymph of the ear and affects function. 6. Pseudotumor Cerebri: Benign, intracranial hypertension characterized by headache and blurred vision may occur rarely in adults. Although discontinuation of the drug reverses this condition, it is not clear whether permanent sequelae may occur. Tetracyclines Adverse Effects: 7. Contraindications: The tetracyclines should not be used in pregnant or breast-feeding women or in children less than 8 years of age. Glycylcyclines Glycylcyclines Glycylcyclines: Tigecycline, a derivative of minocycline, is the first member of the glycylcycline antimicrobial class. It is indicated for the treatment of complicated skin and soft tissue infections, complicated intra-abdominal infections, and community-acquired pneumonia. Glycylcyclines Mechanism of Action: Tigecycline exhibits bacteriostatic action by reversibly binding to the 30S ribosomal subunit and inhibiting bacterial protein synthesis. Antibacterial Spectrum: Tigecycline exhibits broad-spectrum activity that includes methicillin-resistant staphylococci (MRSA), multidrug-resistant streptococci, vancomycin-resistant enterococci (VRE), extended-spectrum β-lactamase–producing gram-negative bacteria, Acinetobacter baumannii, and many anaerobic organisms. Tigecycline is not active against Morganella, Proteus, Providencia, or Pseudomonas species. Glycylcyclines Resistance: Tigecycline was developed to overcome the emergence of tetracycline class–resistant organisms that utilize efflux pumps and ribosomal protection to confer resistance. Resistance to tigecycline has been observed and is primarily attributed to overexpression of efflux pumps. Glycylcyclines Pharmacokinetics: Following IV infusion, tigecycline exhibits a large volume of distribution. It penetrates tissues well but achieves low plasma concentrations. Consequently, tigecycline is a poor option for bloodstream infections. The primary route of elimination is biliary/fecal. No dosage adjustments are necessary for patients with renal impairment; however, a dose reduction is recommended in severe hepatic dysfunction. Glycylcyclines Adverse Effects: Tigecycline is associated with significant nausea and vomiting. Acute pancreatitis, including fatality, has been reported with therapy. Elevations in liver enzymes and serum creatinine may also occur. All-cause mortality in patients treated with tigecycline is higher than with other agents. A boxed warning states that tigecycline should be reserved for use in situations when alternative treatments are not suitable. Glycylcyclines Adverse Effects: Other adverse effects are similar to those of the tetracyclines and include photosensitivity, pseudotumor cerebri, discoloration of permanent teeth when used during tooth development, and fetal harm when administered in pregnancy. Tigecycline may decrease the clearance of warfarin. Therefore, the international normalized ratio should be monitored closely when tigecycline is co-administered with warfarin. Aminoglycosides Aminoglycosides Aminoglycosides: Aminoglycosides are used for the treatment of serious infections due to aerobic gram-negative bacilli; however, their clinical utility is limited due to serious toxicities. Aminoglycosides Mechanism of Action: Aminoglycosides diffuse through porin channels in the outer membrane of susceptible organisms. These organisms also have an oxygen-dependent system that transports the drug across the cytoplasmic membrane. Inside the cell, they bind the 30S ribosomal subunit, where they interfere with assembly of the functional ribosomal apparatus and/or cause the 30S subunit of the completed ribosome to misread the genetic code (Figure 2). Aminoglycosides have concentration-dependent bactericidal activity; that is, their efficacy is dependent on the maximum concentration (Cmax) of drug above the minimum inhibitory concentration (MIC) of the organism. Aminoglycosides Mechanism of Action: For aminoglycosides, the target Cmax is eight to ten times the MIC. They also exhibit a post-antibiotic effect (PAE), which is continued bacterial suppression after drug concentrations fall below the MIC. The larger the dose, the longer the PAE. Because of these properties, high-dose extended-interval dosing is commonly utilized. This dosing strategy also reduces the risk of nephrotoxicity and increases convenience. Aminoglycosides Antibacterial Spectrum: The aminoglycosides are effective for the majority of aerobic gram-negative bacilli, including those that may be multidrug resistant, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp. Additionally, aminoglycosides are often combined with a β-lactam antibiotic to employ a synergistic effect, particularly in the treatment of Enterococcus faecalis and Enterococcus faecium infective endocarditis. Aminoglycosides Resistance: Resistance to aminoglycosides occurs via: 1. Efflux pumps. 2. Decreased uptake, and/or 3. Modification and inactivation by plasmid-associated synthesis of enzymes. Each of these enzymes has its own aminoglycoside specificity; therefore, crossresistance cannot be presumed. Note: Amikacin is less vulnerable to these enzymes than other antibiotics in this group. Aminoglycosides Pharmacokinetics: 1. Absorption: The highly polar, polycationic structure of the aminoglycosides prevents adequate absorption after oral administration; therefore, all aminoglycosides (except neomycin) must be given parenterally to achieve adequate serum concentrations (Figure 8). Aminoglycosides Pharmacokinetics: 1. Absorption: Note: Neomycin is not given parenterally due to severe nephrotoxicity. It is administered topically for skin infections or orally to decontaminate the gastrointestinal tract prior to colorectal surgery. Aminoglycosides Pharmacokinetics: 2. Distribution: Because of their hydrophilicity, aminoglycoside tissue concentrations may be subtherapeutic, and penetration into most body fluids is variable. Concentrations achieved in CSF are inadequate, even in the presence of inflamed meninges. For central nervous system infections, the intrathecal or intraventricular routes may be utilized. All aminoglycosides cross the placental barrier and may accumulate in fetal plasma and amniotic fluid. Aminoglycosides Pharmacokinetics: 3. Elimination: More than 90% of the parenteral aminoglycosides are excreted unchanged in the urine (Figure 8). Accumulation occurs in patients with renal dysfunction; thus, dose adjustments are required. Neomycin is primarily excreted unchanged in the feces. Aminoglycosides Figure 8 – Administration and fate of aminoglycosides. CNS = central nervous system. Aminoglycosides Adverse Effects: Therapeutic drug monitoring of gentamicin, tobramycin, and amikacin plasma concentrations is imperative to ensure appropriateness of dosing and to minimize doserelated toxicities (Figure 9). The elderly are particularly susceptible to nephrotoxicity and ototoxicity. Aminoglycosides Figure 9 – Some adverse effects of aminoglycosides. Aminoglycosides Adverse Effects: 1. Ototoxicity: Ototoxicity (vestibular and auditory) is directly related to high peak plasma concentrations and the duration of treatment. Aminoglycosides accumulate in the endolymph and perilymph of the inner ear. Deafness may be irreversible and has been known to affect developing fetuses. Patients simultaneously receiving concomitant ototoxic drugs, such as cisplatin or loop diuretics, are particularly at risk. Vertigo (especially in patients receiving streptomycin) may also occur. Aminoglycosides Adverse Effects: 2. Nephrotoxicity: Retention of the aminoglycosides by the proximal tubular cells disrupts calciummediated transport processes. This results in kidney damage ranging from mild, reversible renal impairment to severe, potentially irreversible acute tubular necrosis. Aminoglycosides Adverse Effects: 3. Neuromuscular Paralysis: This adverse effect is associated with a rapid increase in concentration (for example, high doses infused over a short period) or concurrent administration with neuromuscular blockers. Patients with myasthenia gravis are particularly at risk. Prompt administration of calcium gluconate or neostigmine can reverse the block that causes neuromuscular paralysis. 4. Allergic Reactions: Contact dermatitis is a common reaction to topically applied neomycin. Macrolides and Ketolides Macrolides and Ketolides Macrolides and Ketolides: The macrolides are a group of antibiotics with a macrocyclic lactone structure to which one or more deoxy sugars are attached. Erythromycin was the first of these drugs to have clinical application, both as a drug of first choice and as an alternative to penicillin in individuals with an allergy to βlactam antibiotics. Clarithromycin (a methylated form of erythromycin) and azithromycin (having a larger lactone ring) have some features in common with, and others that improve upon, erythromycin. Telithromycin, a semisynthetic derivative of erythromycin, is a “ketolide” antimicrobial agent (no longer used in the United States). Macrolides and Ketolides Mechanism of Action: The macrolides and ketolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting translocation steps of protein synthesis (Figure 2). They may also interfere with other steps, such as transpeptidation. Generally considered to be bacteriostatic, they may be bactericidal at higher doses. Their binding site is either identical to or in close proximity to that for clindamycin and chloramphenicol. Macrolides and Ketolides Antibacterial Spectrum: 1. Erythromycin: This drug is effective against many of the same organisms as penicillin G , therefore, it may be considered as an alternative in patients with penicillin allergy. 2. Clarithromycin: Clarithromycin has activity similar to erythromycin, but it is also effective against Haemophilus influenzae and has greater activity against intracellular pathogens such as Chlamydia, Legionella, Moraxella, Ureaplasma species, and Helicobacter pylori. Macrolides and Ketolides Macrolides and Ketolides Antibacterial Spectrum: 3. Azithromycin: Although less active than erythromycin against streptococci and staphylococci, azithromycin is far more active against respiratory pathogens such as H. influenzae and Moraxella catarrhalis. Extensive use of azithromycin has resulted in growing Streptococcus pneumoniae resistance. 4. Telithromycin: Telithromycin has an antimicrobial spectrum similar to that of azithromycin. Moreover, the structural modification within ketolides neutralizes the most common resistance mechanisms that render macrolides ineffective. Macrolides and Ketolides Resistance: Resistance to macrolides is associated with: 1. The inability of the organism to take up the antibiotic. 2. The presence of efflux pumps. 3. A decreased affinity of the 50S ribosomal subunit for the antibiotic due to methylation of an adenine in the 23S bacterial ribosomal RNA in gram-positive organisms. 4. The presence of plasmid-associated erythromycin esterases in gram-negative organisms such as the Enterobacteriaceae. Macrolides and Ketolides Resistance: Erythromycin has limited clinical use due to increasing resistance. Both clarithromycin and azithromycin share some cross-resistance with erythromycin. Telithromycin may be effective against macrolide-resistant organisms. Macrolides and Ketolides Pharmacokinetics: 1. Absorption: The erythromycin base is destroyed by gastric acid; thus, either enteric-coated tablets or esterified forms of the antibiotic are administered and all have adequate oral absorption (Figure 11). Clarithromycin, azithromycin, and telithromycin are stable in stomach acid and are readily absorbed. Food interferes with the absorption of erythromycin and azithromycin but can increase that of clarithromycin. Telithromycin is administered orally without regard to meals. Erythromycin and azithromycin are available in IV formulations. Macrolides and Ketolides Figure 11 – Administration and fate of the macrolide antibiotics. CNS = central nervous system. Macrolides and Ketolides Pharmacokinetics: 2. Distribution: Erythromycin distributes well to all body fluids except the CSF. It is one of the few antibiotics that diffuse into prostatic fluid, and it also accumulates in macrophages. All four drugs concentrate in the liver. Clarithromycin, azithromycin, and telithromycin are widely distributed in the tissues. Azithromycin concentrates in neutrophils, macrophages, and fibroblasts, and serum concentrations are low. It has the largest volume of distribution of the four drugs Macrolides and Ketolides Pharmacokinetics: 3. Elimination: Erythromycin and telithromycin undergo hepatic metabolism. They inhibit the oxidation of a number of drugs through their interaction with the cytochrome P450 system. Interference with the metabolism of drugs such as theophylline, statins, and numerous antiepileptics has been reported for clarithromycin. Macrolides and Ketolides Pharmacokinetics: 4. Excretion: Azithromycin is primarily concentrated and excreted in the bile as active drug. Erythromycin and its metabolites are also excreted in the bile (Figure 11). Partial reabsorption occurs through the enterohepatic circulation. In contrast, clarithromycin is hepatically metabolized, and the active drug and its metabolites are mainly excreted in the urine. The dosage of this drug should be adjusted in patients with renal impairment. Macrolides and Ketolides Adverse Effects: 1. Gastric Distress and Motility: Gastrointestinal upset is the most common adverse effect of the macrolides and may lead to poor patient compliance (especially with erythromycin). The other macrolides seem to be better tolerated (Figure 13). Higher doses of erythromycin lead to smooth muscle contractions that result in the movement of gastric contents to the duodenum, an adverse effect sometimes employed for the treatment of gastroparesis or postoperative ileus. Macrolides and Ketolides Adverse Effects: Figure 13 – Some adverse effects of macrolide antibiotics. Macrolides and Ketolides Adverse Effects: 2. Cholestatic Jaundice: This adverse effect occurs most commonly with the estolate form of erythromycin (not used in the United States); however, it has been reported with other formulations and other agents in this class. 3. Ototoxicity: Transient deafness has been associated with erythromycin, especially at high dosages. Azithromycin has also been associated with irreversible sensorineural hearing loss. Macrolides and Ketolides Adverse Effects: 4. QTc Prolongation: Macrolides and ketolides may prolong the QTc interval and should be used with caution in those patients with proarrhythmic conditions or concomitant use of proarrhythmic agents. 5. Contraindications: Patients with hepatic dysfunction should be treated cautiously with erythromycin, telithromycin, or azithromycin, because these drugs accumulate in the liver. Severe hepatotoxicity with telithromycin has limited its use, given the availability of alternative therapies. Macrolides and Ketolides Adverse Effects: 6. Drug Interactions: Erythromycin, telithromycin, and clarithromycin inhibit the hepatic metabolism of a number of drugs, which can lead to toxic accumulation of these compounds (Figure 14). An interaction with digoxin may occur. One theory to explain this interaction is that the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, leading to greater reabsorption of digoxin from the enterohepatic circulation. Macrolides and Ketolides Figure 14 – Inhibition of the cytochrome P450 system by erythromycin, clarithromycin, and telithromycin. Fidaxomicin Fidaxomicin Fidaxomicin: Fidaxomicin is a macrocyclic antibiotic with a structure similar to the macrolides; however, it has a unique mechanism of action. Fidaxomicin acts on the sigma subunit of RNA polymerase, thereby disrupting bacterial transcription, terminating protein synthesis and resulting in cell death in susceptible organisms. Fidaxomicin has a very narrow spectrum of activity limited to gram-positive aerobes and anaerobes. While it possesses activity against staphylococci and enterococci, it is used primarily for its bactericidal activity against Clostridium difficile. Fidaxomicin Fidaxomicin: Because of the unique target site, cross-resistance with other antibiotic classes has not been documented. Following oral administration, fidaxomicin has minimal systemic absorption and primarily remains within the gastrointestinal tract. This is ideal for the treatment of C. difficile infection, which occurs in the gut. The most common adverse effects include nausea, vomiting, and abdominal pain. Anemia and neutropenia have been observed infrequently. Hypersensitivity reactions including angioedema, dyspnea, and pruritus have occurred. Fidaxomicin Fidaxomicin: Fidaxomicin should be used with caution in patients with a macrolide allergy, as they may be at increased risk for hypersensitivity. Chloramphenicol Chloramphenicol Chloramphenicol: The use of chloramphenicol, a broad-spectrum antibiotic, is restricted to life-threatening infections for which no alternatives exist. Chloramphenicol Mechanism of Action: Chloramphenicol binds reversibly to the bacterial 50S ribosomal subunit and inhibits protein synthesis at the peptidyl transferase reaction. Because of some similarity of mammalian mitochondrial ribosomes to those of bacteria, protein and ATP synthesis in these organelles may be inhibited at high circulating chloramphenicol concentrations, producing bone marrow toxicity. Note: The oral formulation of chloramphenicol was removed from the US market due to this toxicity. Chloramphenicol Antibacterial Spectrum: Chloramphenicol is active against many types of microorganisms including chlamydiae, rickettsiae, spirochetes, and anaerobes. The drug is primarily bacteriostatic, but it may exert bactericidal activity depending on the dose and organism. Resistance: Resistance is conferred by the presence of enzymes that inactivate chloramphenicol. Other mechanisms include decreased ability to penetrate the organism and ribosomal binding site alterations. Chloramphenicol Pharmacokinetics: Chloramphenicol is administered intravenously and is widely distributed throughout the body. It reaches therapeutic concentrations in the CSF. Chloramphenicol primarily undergoes hepatic metabolism to an inactive glucuronide, which is secreted by the renal tubule and eliminated in the urine. Dose reductions are necessary in patients with liver dysfunction or cirrhosis. Chloramphenicol is also secreted into breast milk and should be avoided in breastfeeding mothers. Chloramphenicol Adverse Effects: 1. Anemias: Patients may experience dose-related anemia, hemolytic anemia (observed in patients with glucose-6-phosphate dehydrogenase deficiency), and aplastic anemia. Note: Aplastic anemia is independent of dose and may occur after therapy has ceased. Chloramphenicol Adverse Effects: 2. Gray Baby Syndrome: Neonates have a low capacity to glucuronidate the antibiotic, and they have underdeveloped renal function, which decreases their ability to excrete the drug. This leads to drug accumulation to concentrations that interfere with the function of mitochondrial ribosomes, causing poor feeding, depressed breathing, cardiovascular collapse, cyanosis (hence the term “gray baby”), and death. Adults who have received very high doses of chloramphenicol may also exhibit this toxicity. Chloramphenicol Chloramphenicol Adverse Effects: 3. Drug Interactions: Chloramphenicol inhibits some of the hepatic mixed-function oxidases, preventing the metabolism of drugs such as warfarin and phenytoin, which may potentiate their effects. Clindamycin Clindamycin Clindamycin: Clindamycin has a mechanism of action that is similar to that of the macrolides. Clindamycin is used primarily in the treatment of infections caused by gram-positive organisms, including MRSA and streptococcus, and anaerobic bacteria. Resistance mechanisms are the same as those for erythromycin, and cross-resistance has been described. C. difficile is resistant to clindamycin, and the utility of clindamycin for gram-negative anaerobes (for example, Bacteroides sp.) is decreasing due to increasing resistance. Clindamycin is available in both IV and oral formulations, but use of oral clindamycin is limited by gastrointestinal intolerance. Clindamycin Clindamycin: It distributes well into all body fluids but exhibits poor entry into the CSF. Clindamycin undergoes extensive oxidative metabolism to active and inactive products and is excreted into bile and urine. Low urinary excretion of active drug limits its clinical utility for urinary tract infections. Accumulation has been reported in patients with either severe renal impairment or hepatic failure. In addition to skin rash, the most common adverse effect is diarrhea, which may represent a serious pseudomembranous colitis caused by overgrowth of C. difficile. Clindamycin Clindamycin: Oral administration of either metronidazole or vancomycin is usually effective in the treatment of C. difficile infection. Clindamycin Figure 15 – Administration and fate of clindamycin. Quinupristin/Dalfopristin Quinupristin/Dalfopristin Quinupristin/Dalfopristin: Quinupristin/dalfopristin is a mixture of two streptogramins in a ratio of 30 to 70, respectively. Due to significant adverse effects, this combination drug is normally reserved for the treatment of severe infections caused by vancomycin-resistant Enterococcus faecium (VRE) in the absence of other therapeutic options. Quinupristin/Dalfopristin Mechanism of Action: Each component of this combination drug binds to a separate site on the 50S bacterial ribosome. Dalfopristin disrupts elongation by interfering with the addition of new amino acids to the peptide chain. Quinupristin prevents elongation similar to the macrolides and causes release of incomplete peptide chains. Thus, they synergistically interrupt protein synthesis. The combination drug has bactericidal activity against most susceptible organisms and has a long PAE. Quinupristin/Dalfopristin Antibacterial Spectrum: Quinupristin/dalfopristin is active primarily against gram-positive cocci, including those resistant to other antibiotics. Its primary use is for the treatment of E. faecium infections, including VRE strains, against which it is bacteriostatic. The drug is not effective against E. faecalis. Quinupristin/Dalfopristin Resistance: Enzymatic processes commonly account for resistance to these agents. For example, the presence of a ribosomal enzyme that methylates the target bacterial 23S ribosomal RNA site can interfere in quinupristin binding. In some cases, the enzymatic modification can change the action from bactericidal to bacteriostatic. Plasmid-associated acetyltransferase inactivates dalfopristin. An active efflux pump can also decrease levels of the antibiotics in bacteria. Quinupristin/Dalfopristin Pharmacokinetics: Quinupristin/dalfopristin is available intravenously. It does not achieve therapeutic concentrations in CSF. Both compounds undergo hepatic metabolism, with excretion mainly in the feces. Quinupristin/Dalfopristin Adverse Effects: Venous irritation commonly occurs when quinupristin/dalfopristin is administered through a peripheral rather than a central line. Hyperbilirubinemia occurs in about 25% of patients, resulting from a competition with the antibiotic for excretion. Arthralgia and myalgia have been reported when higher doses are administered. Quinupristin/dalfopristin inhibits the cytochrome P450 CYP3A4 isoenzyme, and concomitant administration with drugs that are metabolized by this pathway may lead to toxicities. Oxazolidinones Oxazolidinones Oxazolidinones: Linezolid and tedizolid are synthetic oxazolidinones developed to combat gram-positive organisms, including resistant isolates such as methicillin-resistant Staphylococcus aureus, VRE, and penicillin-resistant streptococci. Oxazolidinones Mechanism of Action: Linezolid and tedizolid bind to the bacterial 23S ribosomal RNA of the 50S subunit, thereby inhibiting the formation of the 70S initiation complex and translation of bacterial proteins. Oxazolidinones Antibacterial Spectrum: The antibacterial action of the oxazolidinones is directed primarily against grampositive organisms such as staphylococci, streptococci, and enterococci, Corynebacterium species and Listeria monocytogenes. It is also moderately active against Mycobacterium tuberculosis. The main clinical use of linezolid and tedizolid is to treat infections caused by drugresistant gram-positive organisms. Like other agents that interfere with bacterial protein synthesis, linezolid and tedizolid are bacteriostatic; however, linezolid has bactericidal activity against streptococci. Oxazolidinones Antibacterial Spectrum: Linezolid is an alternative to daptomycin for infections caused by VRE. Because they are bacteriostatic, the oxazolidinones are not recommended as first-line treatment for MRSA bacteremia. Resistance: Resistance primarily occurs via reduced binding at the target site. Reduced susceptibility and resistance have been reported in S. aureus and Enterococcus sp. Cross-resistance with other protein synthesis inhibitors does not occur. Oxazolidinones Pharmacokinetics: Linezolid and tedizolid are well absorbed after oral administration. IV formulations are also available. These drugs distribute widely throughout the body. Although the metabolic pathway of linezolid has not been fully determined, it is known that it is metabolized via oxidation to two inactive metabolites. The drug is excreted both by renal and nonrenal routes. Tedizolid is metabolized by sulfation, and the majority of elimination occurs via the liver, and drug is mainly excreted in the feces. No dose adjustments are required for either agent for renal or hepatic dysfunction. Oxazolidinones Adverse Effects: The most common adverse effects are gastrointestinal upset, nausea, diarrhea, headache, and rash. Thrombocytopenia has been reported, usually in patients taking the drug for longer than 10 days. Linezolid and tedizolid possess nonselective monoamine oxidase activity and may lead to serotonin syndrome if given concomitantly with large quantities of tyraminecontaining foods, selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors. Oxazolidinones Adverse Effects: The condition is reversible when the drug is discontinued. Irreversible peripheral neuropathies and optic neuritis causing blindness have been associated with greater than 28 days of use, limiting utility for extended-duration treatments.