PrAMPs are products of the innate immune system and provide a first line of defense against invading bacteria. To date, PrAMPs have been found in many arthropods, such as insects and crustaceans, as well as in some mammals, such as cows, pigs, goats and sheep Scocchi et al. Subsequently, it was shown, however, that PrAMPs are equally effective at inhibiting bacterial strains where the gene encoding DnaK was inactivated Krizsan et al.
This suggested that another intracellular target for PrAMPs must exist. Indeed, PrAMPs were shown to bind to ribosomes and inhibit protein synthesis in vivo and in vitro Krizsan et al. Despite the diverse array of PrAMPs that have been so far identified, only a subset has been mechanistically investigated. Of the characterized PrAMPs, two distinct mechanisms of action have been identified, both of which involve inhibition of protein synthesis. Other studied type I insect PrAMPs include pyrrhocoricin from the firebeetle Pyrrhocoris apterus and metalnikowin-1 from the green shield bug Palomena prasina.
Structural studies have revealed that type I PrAMPs bind within the ribosomal exit tunnel located on the large subunit Roy et al. The orientation of type I PrAMPs is inverted with respect to a nascent polypeptide chain, such that the N-terminus is located at the peptidyl transferase center PTC and the C-terminus extends into the ribosomal tunnel.
Consistent with biochemical studies Seefeldt et al. Figure 9. PrAMP and klebsazolicin antibiotics bind within the ribosomal exit tunnel. The best-characterized member is Api, a derivative of the naturally occurring PrAMP apidaecin 1b from the honey bee Apis mellifera.
Apideacin-like PrAMPs are also found in other bees, wasps and hornets. Biochemical studies show that Api does not inhibit translation initiation or elongation despite the overlap in binding site with the growing nascent polypeptide chain Figure 9F.
This paradox was resolved by the finding that Api has a very low affinity for empty ribosomes and require the presence of a termination release factor, RF1 or RF2, for stable binding Florin et al. In fact, release of the polypeptide is a pre-requisite to allow Api to enter the ribosomal tunnel and engage its binding site.
Specifically, Arg17 of Api can form direct hydrogen bond H-bond interactions with the sidechain of glutamine Q of the conserved GGQ motif. This is consistent with biochemical findings showing that mutations of Arg17 in Api decrease the ribosome affinity and reduce its inhibitory properties Krizsan et al. It should be noted that the number of ribosomes within a bacterial cell, such as E.
Nevertheless, this leads to a rapid depletion of the free pools of RF1 and RF2 in the cell, such that the vast majority of ribosomes become stalled during translation termination. Because of the absence of RF1 and RF2, an increased level of stop codon readthrough is observed on the termination stalled ribosomes. Surprisingly, the stop codon readthrough induced by Api is considerably higher than that induced by the classical misreading antibiotic streptomycin Florin et al. Thus, in summary, type II PrAMPs such as Api, have a dual mode of action to, on one hand, trap RF1 and RF2 on a minority of ribosomes within the cell and, on the other hand, to stall the majority of ribosomes at the termination phase due to the absence of available RFs, which in turn increases the rates of stop codon readthrough.
Klebsazolicin KLB is the first member of a new class of protein synthesis inhibitors, which comes from the opportunistic human pathogen Klebsiella pneumonia , and was discovered recently using a genome mining approach Metelev et al. This method allows one to harness a much greater chemical diversity and can result in the discovery of entirely new molecular scaffolds. Analysis of genomic data makes it possible to identify gene clusters encoding biosynthetic pathways for potential drug candidates, which may otherwise escape attention due to their inactivity under laboratory growth conditions Doroghazi et al.
Ribosomally-synthesized post-translationally modified peptides RiPPs are among the most abundant antimicrobial agents synthesized by various bacteria, including human microbiota Donia et al. KLB is the first linear azole-containing RiPP for which the mode of binding to its target, the bacterial ribosome Figures 9A,G , has been structurally characterized. KLB is synthesized on the ribosome as a precursor, which undergoes post-translational modifications by dedicated enzymes encoded in a compact gene cluster Metelev et al.
KLB appears to have a modular structure: its 14 N-terminal residues are essential for the inhibition of the ribosome, while its nine C-terminal residues are likely to be important for the uptake of the molecule and are not essential for ribosome binding Metelev et al.
Moreover, KLB can be expressed in a surrogate E. Structural analysis of the ribosome-KLB complex reveals that the compound binds in the nascent peptide exit tunnel to a site that overlaps with the binding sites of macrolides, S B , the PrAMPs, and significantly obstructs the tunnel Figure 9G ; Metelev et al. KLB inhibits protein synthesis by blocking the elongation after only three amino acids of the nascent peptide have been polymerized Metelev et al.
The KLB binding site does not overlap with the aminoacyl moieties of the A- and P-site tRNAs Figure 9G and the main occlusion point occurs around the macrolide binding site leaving some space between the PTC active site and the bound KLB molecule, so that the 2—3 amino acid long nascent peptide can fit. For example, it forms two H-bonds with U, which resembles a non-canonical U-U base-pair.
There are an array of different thiopeptide antibiotics that inhibit translation either by interacting with translation factor EF-Tu, for example, GEA, or by directly binding to the ribosome, with the best characterized being thiostrepton, nosiheptide, and micrococcin Bagley et al.
These antibiotics are synthesized as precursor polypeptides by the ribosome and then are post-translationally modified to yield the active compound Wieland Brown et al. The chemical structure of thiostrepton can be separated into two loops loop1 and 2 and a dehydroalanine tail, which are linked together by a tetrahydro-pyridinylamine moiety Figure 10A.
The 16 distinct chemical moieties that comprise thiostrepton include many thiazole rings as well as non-canonical and canonical amino acids, including for example, threonine, isoleucine, alanine and dehydroalanine Figure 10A ; Kelly et al.
The thiopeptide antibiotics are effective against Gram-positive bacteria, in particular, methicillin-resistant Staphlococcus aureus MRSA , as well as against the malarial parasite Plasmodium falciparum Aminake et al. Figure Thiostrepton binding site on the large ribosomal subunit. A Chemical structure of the thiostrepton. The 50S subunit is viewed from the subunit interface as indicated by the inset at the top left. C Close-up view of the thiostrepton binding site showing its interactions with 23S rRNA nucleotides A and A located at the tips of helices H43 and H44 cyan as well as proline residues orange within the N-terminal domain NTD of ribosomal protein uL11 green.
The crystal structure of the Deinococcus radiodurans large subunit bound to thiostrepton as well as nosiheptide and micrococcin; Harms et al. The solution NMR structure of thiostrepton compares well with the X-ray structure and reveals high flexibility of the dehydroalanine tail Jonker et al.
Within the cleft, thiostrepton interacts with nucleotides A and A, located at the tips of H43 and H44, respectively, and the thiazole rings of thiostrepton stack upon the proline residues located in the NTD of uL11 Figure 10C. This thiopeptide binding site is distinct when compared to other clinically used antibiotics and therefore cross-resistance with thiopeptides has not been reported.
Nevertheless, mutations in A, A, or in the numerous proline residues of the uLNTD reduce thiopeptide binding and confer drug-resistance in bacteria and archaea Wilson, ; Baumann et al. Eukaryotic 80S ribosomes are naturally resistant to thiostrepton, most probably due to sequence differences in uL11, which is in agreement with the observations that yeast 80S ribosomes bearing bacterial uL11 are sensitive to the drug Garcia-Marcos et al.
Consistently, thiostrepton has been reported to inhibit IF2-dependent initiation complex formation Brandi et al. The available structures of peptide antibiotics on the ribosome illustrate the diverse manners in which these inhibitors interact with the ribosome and interfere with translation.
High-resolution structures now open the way for structure-based design to develop peptide antibiotics with improved properties by identifying sites that can be modified to enable additional interaction with the ribosome. Similarly, the structures also identify residues that are not critical for ribosome binding and therefore can be utilized to optimize parameters such as uptake and retention, serum stability as well as reduced membrane permeabilization and toxicity. The proximity of the binding sites of peptide antibiotics on the ribosome in relation to other classes of ribosome-targeting antibiotics Figures 11A,B also offers the opportunity to generate hybrid compounds that span over multiple binding sites.
The increase in sequenced genomes coupled with improved data mining algorithms is leading to the identification of potential gene clusters encoding biosynthetic pathways for novel peptide antibiotics and PrAMPs. It will be interesting to see what novel ribosome-targeting peptide antibiotics these approaches will yield and to investigate their binding sites on the ribosome and mechanism of action to inhibit translation.
Relative location of peptide and small-molecular antibiotics on the bacterial ribosome. A Overview of the binding sites of the peptide yellow and small-molecular blue antibiotics targeting the small 30S ribosomal subunit: edeine B, GE, dityromycin, viomycin, odilorhabdin, negamycin, tetracycline, paromomycin, streptomycin, spectinomycin, amicoumacin, pactamycin, kasugamycin.
B Overview of the binding sites of the peptide yellow and small-molecular blue antibiotics targeting the large 50S ribosomal subunit: streptogramin type A dalfoprsitin and type B quinupristin , oncocin, apidaecin, klebsazolicin, thiostrepton, orthosomycin avilamycin , macrolides erythromycin, carbomycin, spiramycin, tylosin , chloramphenicol, hygromycin A, AA, lincosamides clindamycin , oxazolidinones linezolid.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We thank Dr. Maxim Svetlov for critical reading of the manuscript and valuable suggestions. Agarwal, D.
Error-prone and error-restrictive mutations affecting ribosomal protein S Akbergenov, R. Molecular basis for the selectivity of antituberculosis compounds capreomycin and viomycin.
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Bagley, M. Thiopeptide antibiotics. Baumann, S. Molecular determinants of microbial resistance to thiopeptide antibiotics. Binz, T. Insights into an unusual nonribosomal peptide synthetase biosynthesis: identification and characterization of the GE biosynthetic gene cluster.
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Champney, W. Bacterial ribosomal subunit synthesis: a novel antibiotic target. Chen, Y. The kinetic mechanism of bacterial ribosome recycling. Nucleic Acids Res. Chinali, G. The action of virginiamycin M on the acceptor, donor, and catalytic sites of peptidyltransferase. PubMed Abstract Google Scholar. Cornish, P. Spontaneous intersubunit rotation in single ribosomes. Cell 30, — Cukras, A. Cell 12, — Delgado, G. Quinupristin-dalfopristin: an overview.
Pharmacotherapy 20, — Depardieu, F. Mutation in 23S rRNA responsible for resistance to membered macrolides and streptogramins in Streptococcus pneumoniae. Dinos, G. Dissecting the ribosomal inhibition mechanisms of edeine and pactamycin: the universally conserved residues G and C regulate P-site tRNA binding.
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A roadmap for natural product discovery based on large-scale genomics and metabolomics. Ermolenko, D. Observation of intersubunit movement of the ribosome in solution using FRET. Fabbretti, A. Florin, T. An antimicrobial peptide that inhibits translation by trapping release factors on the ribosome. Gagnon, M. Structures of proline-rich peptides bound to the ribosome reveal a common mechanism of protein synthesis inhibition.
Gale, E. Gao, N. Garcia-Marcos, A. In vivo assembling of bacterial ribosomal protein L11 into yeast ribosomes makes the particles sensitive to the prokaryotic specific antibiotic thiostrepton. Garreau de Loubresse, N. Structural basis for the inhibition of the eukaryotic ribosome. Nature , — Gonzalez, R. Thiostrepton inhibition of tRNA delivery to the ribosome. Please log in to CEUfast to enable the course progress and auto resume features.
This peer reviewed course is applicable for the following professions:. This course will be updated or discontinued on or before Wednesday, February 15, After completing this educational program, the learner will be able to: Describe the mechanism of action for each group of protein synthesis inhibitors. Discuss indications and usage for each group of protein synthesis inhibitors. Discuss the specific warnings and precautions for each group of protein synthesis inhibitors.
Describe the specific patient parameters that should be assessed before administering each group of protein synthesis inhibitors. Relate the contraindications for each protein synthesis inhibitors. CEUFast Inc. The Planning Committee and Authors do not have any conflict of interest.
Protein Synthesis Inhibitors. Complete Course. Options Back Complete Course Print. Time Remaining:. Nursing Assistants from California, only. You must read the material on this page before you can take the test. The California Department of Public Health, Training Program Review Unit has determined that is the only way to prove that you actually spent the time to read the course.
Protein Synthesis Inhibitors A protein synthesis inhibitor is an antibiotic that stops or slows the growth of new proteins. Aminoglycosides Tetracycline and glycylcycline Oxazolidinones Amphenicols and pleuromutilins Macrolides and ketolides Lincosamides Streptogramins Protein system inhibitors are toxic and require close monitoring.
Indications and Use NIH, h NIH, a, b, f, i, l In general, aminoglycosides are active across a broad spectrum of aerobic gram-negative and gram-positive organisms and mycobacteria. Microbiology Aerobic gram-negative organisms: Acinetobacter spp Enterobacteriaceae Haemophilus influenza Neisseria gonorrhoeae Pseudomonas aeruginosa Pseudomonas spp Serratia spp Aerobic gram-positive organisms: Staphylococcus aureus Pneumococci - Aminoglycoside activity is generally considered insufficient for clinical application against these organisms.
Clinical Indications The widespread clinical use of parenteral aminoglycosides is generally limited because less toxic agents with comparable efficacy are available. Monotherapy Aminoglycosides should not be relied upon as monotherapy in infections that involve the lungs, abscesses, and the central nervous system because of poor activity or penetration into these sites. These include: Non-pharyngeal gonococcal infections secondary to Neisseria gonorrhoeae in patients who have a severe penicillin allergy Plague Yersinia pestis Tularemia Urinary tract infections due to multidrug-resistant gram-negative organisms Prophylactic use of aminoglycosides is used in surgical procedures involving the gastrointestinal, urinary tract, or female genital tract in patients with beta-lactam allergies.
Combination Therapy Aminoglycosides are not active alone against Streptococci and Enterococci. Aminoglycosides may be combined with other antibiotics for the following organisms: Mycobacteria Mycobacterium abscessus Mycobacterium chelonae Mycobacterium fortuitum Mycobacterium tuberculosis Non-parenteral aminoglycosides i. Other clinical indications and routes of administration of aminoglycosides include: External otitis media, topical Chronic pulmonary infections in cystic fibrosis, inhaled Gram-negative bacillary meningitis, intrathecal and intraventricular Continuous or intermittent peritoneal dialysis-associated peritonitis or intraperitoneal Prosthetic joint infections, impregnated cement formulations.
Pharmacodynamics and Pharmacokinetics. Absorbed neomycin distributes to tissues and concentrates in the renal cortex. With repeated doses, accumulation also occurs in the inner ear.
Parenteral Aminoglycosides Aminoglycosides NIH, a, b, f, i, l Absorption IV, IM: Rapid and complete Time to Peak, Serum Peak serum aminoglycoside concentrations are measured approximately 30 to 60 minutes after completion of an intravenous infusion or 30 to 90 minutes after an intramuscular injection. Distribution Aminoglycosides are systemically distributed to extracellular fluid, including serum, abscesses, ascitic, pericardial, pleural, synovial, lymphatic, and peritoneal fluids.
There is a high concentration of aminoglycosides in the renal cortex reaching concentrations in the urine of to fold that of the serum. Small amounts are distributed into bile, sputum, saliva, and tears.
Aminoglycosides have poor penetration into CSF, eye, bone, biliary tree, bronchial secretions, and prostate tissue via the IV route. Aminoglycosides show poor penetration across the blood-brain barrier even when the meninges are inflamed.
Aminoglycoside distribution is increased in patients with edema, ascites, burns, pregnancy, cystic fibrosis, fluid overload, and decreased patient dehydration. Local installation into the pleural space or peritoneal cavity can result in significant serum concentrations. Dosing Considerations NIH, a, b, f, i, l Improved patient outcomes are correlated with the rapid therapeutic concentrations of aminoglycosides.
Peak serum concentrations are intended to take advantage of the pharmacodynamic properties to optimize the potential for efficacy. Trough concentrations are targeted to avoid concentration-related toxicity. Creatinine Clearance Since aminoglycosides are eliminated primarily by glomerular filtration, renal function affects the rate of drug clearance and affects the optimal dosing interval.
Selection of Dosing Strategy Extended-interval aminoglycoside dosing is often preferred for patients with suspected or documented moderate to severe infections due to gram-negative aerobic bacteria. Because of comparable efficacy and safety, aminoglycosides pharmacodynamic profiles and greater ease of administration include: Bacteremia Febrile neutropenia patients with malignancy adults and children Gynecologic infections including pelvic inflammatory disease Immunocompetent, non-pregnant adults and children older than three months of age with: Intraabdominal infections Postpartum endometritis Respiratory tract infections Soft-tissue infections Urinary tract infections Extended-interval dosing strategies have also been evaluated in patients with cystic fibrosis and for synergistic therapy for patients with select serious gram-positive infections.
Rotate injection sites. Special Circumstances Gentamicin and tobramycin are frequently used for empiric treatment of continuous ambulatory peritoneal dialysis CAPD related peritonitis. Traditional Intermittent Dosing and Monitoring Administration of an initial loading dose is determined by the type or site of infection, for which different peak serum gentamicin or tobramycin concentrations are desired.
Dosing Adjustments In general, changes in the dose will result in proportional changes in peak and trough concentration values.
Extended-Interval Dosing and Monitoring Administration of a higher dose of gentamicin or tobramycin at an extended-interval is dependent on renal function and subsequent monitoring of serum drug concentrations. Traditional Intermittent Dosing and Monitoring Administer a loading dose Subsequent maintenance dose is typically ordered in divided doses every 8 - 12 hours for patients with normal renal function Adjustments in the frequency of administration should be made for reductions in renal function Subsequent monitoring of serum concentrations of amikacin guide dose adjustments.
Extended-Interval Dosing and Monitoring Administration of a loading dose The initial dosing interval is based upon the creatinine clearance Subsequent monitoring of serum concentrations guide dose adjustments Subsequent drug concentration monitoring and dosing interval determination are similar to those for gentamicin and tobramycin without the use of the nomogram.
Streptomycin Dosing in Adults NIH, i The dosing of streptomycin varies based on the indications for its use, like Second-line antituberculous therapy Antimicrobial therapy of native valve endocarditis Treatment of nontuberculous mycobacterial infections of the lung in HIV-negative patients Treatment of tularemia Treatment of plague Streptomycin is approved for intramuscular administration. Intravenous use is not recommended.
Warnings and Precautions NIH, a, b, f, i, l. Contraindications Myasthenia gravis is an absolute contraindication to aminoglycoside use, regardless of the dosing method used. Clinical Concerns Aminoglycoside preparations may contain sulfites that may cause allergic-type reactions and life-threatening or less severe asthmatic episodes in certain individuals.
Use caution in patients with: Pre-existing vertigo, tinnitus, or hearing loss Hypocalcemia Neuromuscular disorders, including myasthenia gravis and Parkinson disease Pre-existing renal insufficiency Some penicillin derivatives may accelerate the degradation of aminoglycosides. Toxicity Aminoglycoside toxicity may cause neurotoxicity.
The auditory changes: Are usually irreversible Are usually bilateral May be partial or total Risk factors for aminoglycoside-induced hearing loss are: Increased with the degree of exposure to either high peak or high trough serum concentrations Increased in patients having preexisting renal damage and in those with a healthy renal function to whom aminoglycosides are administered for longer periods or in higher doses than those recommended Manifestations of vestibular toxicity include: Ataxia Disequilibrium Lightheadedness Nausea Vertigo Vomiting Manifestations of cochlear toxicity are: Hearing loss Tinnitus Ototoxicity is proportional to the amount of drug given and the duration of treatment.
Neurotoxicity may also be manifested by nephrotoxicity. Risk factors include: Pre-existing renal impairment Aminoglycosides administered for longer periods or in higher doses than those recommended Taking concomitant neuro or nephrotoxic medications Advanced age Dehydration Nephrotoxicity may not become apparent until the first few days after cessation of therapy.
Other manifestations of neurotoxicity may include: Numbness Skin tingling Muscle twitching Seizure activity Aminoglycoside toxicity may cause neuromuscular blockade, respiratory failure, and prolonged respiratory paralysis.
Risk factors include administration of aminoglycosides by any route, especially in patients who: Have disease states or concomitant drug therapy that interfere with neuromuscular transmission Receive anesthetics Receive neuromuscular blocking agents such as tubocurarine, succinylcholine, and decamethonium Receive massive transfusions of citrate-anticoagulated blood If a blockage occurs, calcium salts may reverse these phenomena, but mechanical respiratory assistance may be necessary.
Indications and Use NIH, j, c, d, g The tetracyclines and tigecycline are considered broad-spectrum bacteriostatic antibiotics used to treat infection caused by gram-positive and gram-negative bacteria and atypical pathogens. Minocycline distributes in lower concentrations to the bladder, breast, lymph nodes, prostate, and skin. Poor CSF penetration. Deposits in fat for extended periods Tigecycline: therapeutic concentrations have been widely distributed in tissues, gallbladder, lung, and colon All the tetracyclines and tigecycline cross the placenta and accumulate in the bone and teeth of the fetus.
Dosing Considerations NIH, j, c, d, g NIH, k Dosing of each tetracycline and tigecycline antibiotic depends on the susceptible infection and the therapeutic agent appropriate for that infection.
Dosing: Hepatic Impairment Dose adjustment is only required in severe hepatic dysfunction for doxycycline and tigecycline maintenance dose 25 mg IV every 12 hours Hepatotoxicity has been reported Use with caution. Administration Oral Administration Administer oral tetracyclines on an empty stomach i.
Do not chew, crush, or split For doxycyclines, follow the directions for taking the specific therapeutic agent on an empty stomach or with food. IV Administration Infuse over 30 to 60 minutes up to 4 hours depending on the therapeutic agent through a dedicated line or Y-site If the same IV line is used for several drugs' sequential, flush the line with an appropriate compatible solution both before and after administration Avoid rapid administration and extravasation IV administration should be used only if the oral route is not feasible or adequate Prolonged intravenous therapy may be associated with thrombophlebitis.
Patients completing a regimen may still transmit the infection to mosquitoes outside endemic areas Periodontitis: Effectiveness of doxycycline has not been established in patients with coexistent oral candidiasis Use with caution in patients with a history or predisposition to oral candidiasis The absorption of tetracyclines can be impaired by co-administered minerals and antacids e. Concerns Related to Special Populations Pregnancy Do not use during pregnancy In addition to affecting the fetus's tooth development, tetracycline use has been associated with retardation of skeletal development and reduced bone growth As a class, tetracyclines are generally considered second-line antibiotics in pregnant women, and their use should be avoided The decision to continue or discontinue breast-feeding during therapy should consider the risk of exposure to the infant and the benefits of treatment to the mother Pediatric Safety and efficacy in children and adolescents less than 18 years of age have not been established due to increased mortality observed in adult patients' trials Use is only restricted if no alternative antibiotics are available Because of effects on tooth development yellow-gray-brown discoloration , use in patients eight years of age or younger is not recommended.
Dietary Considerations Ethanol: Chronic ethanol ingestion may reduce the serum concentration of doxycycline Tetracyclines in general : Take with food if gastric irritation occurs Doxycycline serum levels may be slightly decreased if taken with food or milk Administration with iron or calcium may decrease doxycycline absorption.
May decrease absorption of calcium, iron, magnesium, zinc, and amino acids Administration on an empty stomach is not recommended due to GI intolerance. This adverse reaction of demeclocycline has been used as a therapeutic advantage in the off-label use of hyponatremia associated with SIADH Autoimmune Syndromes Lupus-like, hepatitis, and vasculitis autoimmune syndromes including serum sickness [e. Indications and Use NIH, u, y.
Microbiology Linezolid is a synthetic oxazolidinone with activity against various gram-positive organisms that are often the causative agent in nosocomial pneumonia, community-acquired pneumonia, and complicated skin and skin structure infections. Linezolid and tedizolid have antibacterial activity against susceptible: Gram-positive organisms: Enterococcus Enterococcus faecalis aka, group D streptococcus or GDS including vancomycin-resistant isolates Enterococcus faecium vancomycin-resistant isolates only Staphylococcus Staphylococcus aureus including methicillin-sensitive MSSA and methicillin-resistant MRSA isolates Staphylococcus epidermidis including MRSA isolates Streptococcus Streptococcus agalactiae aka, group B streptococcus or GBS Streptococcus anginosus group including: Streptococcus anginosus Streptococcus intermedius Streptococcus constellatus Streptococcus pneumoniae aka, pneumococcus Streptococcus pyogenes aka, group A streptococcus or GAS Viridans streptococci Gram-negative organisms: Pasteurella Pasteurella multocida.
Clinical Indications Enterococcal infections, vancomycin-resistant Treatment of vancomycin-resistant Enterococcus faecium infections with or without bacterial invasion of the bloodstream Treatment of community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus methicillin-susceptible isolates only Linezolid is also acceptable second-line treatment for community-acquired pneumococcal pneumonia when penicillin resistance is present Treatment of hospital-acquired, healthcare-associated, and ventilator-associated pneumonia caused by Staphylococcus aureus methicillin-susceptible and resistant isolates or Streptococcus pneumoniae U.
Other Uses Bone and joint infections, including chronic osteomyelitis Tuberculosis in combination with other drugs Alternative to vancomycin in the treatment of febrile neutropenia in cancer patients when a gram-positive infection is suspected Linezolid appears superior to vancomycin in treating community-acquired MRSA infections of the central nervous system Linezolid is also one of few antibiotics that diffuse into the vitreous humor and may, therefore, be effective in treating endophthalmitis inflammation of the inner linings and cavities of the eye caused by susceptible bacteria.
Off-label Uses Brain abscess, subdural empyema, and spinal epidural abscess Staphylococcus aureus [methicillin-resistant] Infective endocarditis Meningitis caused by: Staphylococcus aureus methicillin-resistant VRE: Linezolid is the first-line drug of choice MRSA: Linezolid is an alternative to vancomycin.
Osteomyelitis Staphylococcus aureus [methicillin-resistant] Prosthetic joint infections Septic arthritis Staphylococcus aureus [methicillin-resistant] Septic thrombosis of the cavernous or dural venous sinus Staphylococcus aureus [methicillin-resistant] Linezolid is not approved for the treatment of catheter-related bloodstream infections. Its metabolites are eliminated predominantly in the urine Phosphatases convert Tedizolid phosphate to tedizolid active, parent drug.
There are no other significant circulating metabolites Half-life Elimination Adults: 4. Two metabolites of linezolid may accumulate in patients with severe renal impairment.
Dosing Considerations NIH, u, y Dosing of each oxazolidinone antibiotic depends on the susceptible infection and the therapeutic agent appropriate for that infection. However, no alternative dosing recommendations are suggested Tedizolid No dosage adjustment is necessary. Administration Administer intravenous over 30 to minutes depending on the therapeutic agent Do not mix or infuse with other medications Do not administer as an IV push or bolus Not for intra-arterial, IM, intrathecal, intraperitoneal, or subcutaneous administration If the same IV line is used for sequential of other drugs, flush the line with an appropriate compatible solution both before and after administration.
Contraindications Linezolid is contraindicated in the following situations: Patients who have had a prior allergic reaction to linezolid Hypersensitivity to linezolid or any of the other components of the formulation Concurrent use of or within two weeks of taking MAO inhibitors Patients who have risk factors for serotonin syndrome Tedizolid There are no contraindications listed in the manufacturer's labeling.
Laboratory and Diagnostics Perform culture and sensitivity testing before initiating therapy and where appropriate during treatment When taking linezolid, monitor baseline CBC with differential then twice weekly, particularly in patients: At increased risk of bleeding With pre-existing myelosuppression Individuals who are taking concomitant medications that cause bone marrow suppression Individuals who require greater than two weeks of therapy With chronic infection who have received previous or concomitant antibiotic therapy Whose visual function may become impaired with extended therapy lasting three months or longer With new-onset visual symptoms, regardless of therapy length With renal impairment, monitor for hematopoietic e.
Limited data in the form of case reports in pediatric and adult patients suggest that linezolid may be useful in treating gram-positive CNS infections that have failed to respond to other treatment options describing successful treatment of documented VRE and Staphylococcus aureus CNS and shunt infections in the literature. MAO inhibition causes levels of the neurotransmitter serotonin to increase. Thus, linezolid has the potential for causing serotonin syndrome, i.
Clinical Indications Chloramphenicol is used to treat serious infections due to organisms resistant to other less toxic antibiotics or when its penetrability into the infection site is clinically superior to other antibiotics to which the organism is sensitive. It is useful in infections caused by: Bacteroides Enterococcus faecium vancomycin-resistant Haemophilus influenza Neisseria meningitides Rickettsia Salmonella Vibrio cholera tetracycline-resistant Chloramphenicol remains the first-choice in the treatment of staphylococcal brain abscesses because of its excellent blood-brain barrier penetration far superior to any of the cephalosporins.
Chloramphenicol is active against the three main bacterial causes of meningitis: Neisseria meningitidis Streptococcus pneumoniae Haemophilus influenzae Chloramphenicol remains the drug of choice in treating meningitis in patients with severe penicillin or cephalosporin allergies.
Chloramphenicol and azidamfenicol have a broad spectrum of activity and have been effective in treating ocular infections caused by several bacteria, including: Escherichia coli Staphylococcus aureus Streptococcus pneumoniae Retapamulin is often indicated for the treatment of impetigo, a skin infection for which patients seek care from dermatologists.
Pharmacodynamics and Pharmacokinetics Amphenicols and Pleuromutilins NIH, o, m, x Absorption Azidamfenicol is absorbed intraocular with some systemic absorption after topical application to the eye The absorption of topical retapamulin is low. Thus, systemic exposure is minimal following topical application to intact but increased when applied to abraded skin. It remains relatively unbound to protein and is a small molecule. It has a large apparent volume of distribution and penetrates effectively into all body tissues, including the brain.
Distribution is not uniform, with the highest liver and kidney concentrations and the lowest in the brain and cerebrospinal fluid. Dosing: Renal Impairment The kidneys excrete most of the chloramphenicol dose as the inactive metabolite, chloramphenicol glucuronate. However, dosage adjustment is unlikely due to low systemic absorption.
Dosing: Hepatic Impairment The liver metabolizes chloramphenicol to chloramphenicol glucuronate which is inactive In liver impairment, the dose of chloramphenicol must, therefore, be reduced No standard dose reduction exists for chloramphenicol in liver impairment, and the dose should be adjusted according to measured plasma chloramphenicol concentrations There are no dosage adjustments provided for hepatic impairment in the manufacturer's labeling for retapamulin.
Drug Interactions to Retapamulin Multiple drug interactions with retapamulin may occur, including those that may increase the serum concentration of retapamulin, especially in young patients such as CYP3A4 inhibitors Atazanavir Clarithromycin Darunavir Indinavir Itraconazole Ketoconazole Lopinavir Nefazodone Nelfinavir Ritonavir Telithromycin Tipranavir Saquinavir. Laboratory and Diagnostics Perform culture and sensitivity testing if possible before initiating therapy and where appropriate during treatment Monitor CBC with differential at baseline and every two days during therapy Monitor periodic liver and renal function tests Monitor serum chloramphenicol drug concentrations at both peak and trough Monitor for superinfections If using retapamulin, monitor for creatine phosphokinase CPK elevation where appropriate.
Disease-Related Concerns Hepatic impairment Use amphenicols with caution in patients with hepatic impairment Reduced dosage and serum concentration monitoring both peak and trough are recommended Renal impairment Use amphenicols with caution in patients with renal impairment Reduced dosage and serum concentration monitoring both peak and trough are recommended. Dietary Considerations Patients may have increased dietary need for riboflavin, pyridoxine, and vitamin B 12 Some products may contain sodium Chloramphenicol increases the absorption of iron.
Concerns Related to Adverse Reactions Amphenicols only Hematologic and Oncologic: Blood Dyscrasias — may occur after both short-term and prolonged therapy Aplastic Anemia Aplastic anemia usually occurs weeks or months after treatment has been stopped, and a genetic predisposition may be involved This effect is rare and sometimes fatal Patients are recommended to have a baseline CBC with a repeat CBC every few days while on treatment Chloramphenicol should be discontinued if the complete blood count drops below 2.
Clinical Indications Azithromycin, clarithromycin, and telithromycin have a broader spectrum of activity than erythromycin. Delayed with food due to differences in absorption Telithromycin: 1 hour Distribution Azithromycin: Extensive tissue distribution Distributes well into skin, lungs, sputum, tonsils, and cervix Penetration into CSF is poor Clarithromycin: Widely distributed into most body tissues. Dosing Considerations NIH, n, p, r, s NIH, z Erythromycin and, to some extent, clarithromycin interact with numerous drugs because they inhibit hepatic metabolism.
Warnings and Precautions NIH, n, p, r, s Discontinue use if allergic reactions occur. Drug-Drug Interactions Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, or alternative therapy selection Avoid concurrent use with strong CYP3A4 inhibitors, thus avoiding the risk of sudden cardiac death.
Limitations of use Azithromycin Azithromycin tablets, oral suspension, Zmax only Not recommended for use in patients with moderate to severe pneumonia with any of the following concomitant conditions: cystic fibrosis, nosocomial infections, known or suspected bacteremia, hospitalized, elderly or debilitated or significant health problems that affect the ability to respond to illness e.
In a retrospective population study of U. Indications and Use NIH, q, t. Microbiology Lincosamides have antibacterial activity against susceptible organisms such as: Gram-positive anaerobes: Actinomyces israelii Clostridium clostridioforme Clostridium perfringens Eubacterium lentum Finegoldia "Peptostreptococcus" magna Micromonas "Peptostreptococcus" micros Peptostreptococcus anaerobius Propionibacterium acnes Staphylococcus aureus Staphylococcus epidermidis Streptococcus agalactiae Streptococcus anginosus Streptococcus mitis Streptococcus oralis Streptococcus pneumoniae Streptococcus pyogenes Gram-negative anaerobes: Bacteroides fragilis Prevotella melaninogenica Fusobacterium necrophorum Fusobacterium nucleatum Prevotella intermedia Prevotella bivia.
High concentrations in bone and urine. No significant levels in CSF, even with inflamed meninges Lincomycin: Distributed in body fluids and tissues including peritoneal fluid, pleural fluid, synovial fluid, bone, bile, aqueous humor eye. Dosing Considerations NIH, q, t The appropriate use of Lincosamides is reserved when treatment with other antibiotics is inappropriate. Dosing: Hepatic Impairment Clindamycin and Lincomycin Mild impairment There are no dosage adjustments provided in the manufacturer's labeling Use with caution Clindamycin Moderate to severe impairment There are no dosage adjustments provided in the manufacturer's labeling In studies of patients with moderate or severe liver disease, the half-life is prolonged.
However, when administered on an every 8-hour schedule, accumulation should rarely occur In severe liver disease, use caution and monitor liver enzymes periodically during therapy. Administration Oral Lincomycin Administer with a full glass of water to minimize esophageal ulceration Give around-the-clock to promote less variation in peak and trough serum level Coadministration with food does not adversely affect the absorption of clindamycin-flavored granules Intravaginal and Topical Clindamycin Intravaginal: Points to Remember Vaginal products may weaken condoms or contraceptive diaphragms.
Contraindications Hypersensitivity to clindamycin, lincomycin, or any component of the formulation Patients with a history of CDAD Clostridium difficile-associated diarrhea , regional enteritis, ulcerative colitis Not appropriate for use in the treatment of meningitis due to inadequate penetration into the cerebrospinal fluid.
Laboratory and Diagnostics Perform culture and sensitivity testing if possible before initiating therapy and where appropriate during treatment Observe for changes in bowel frequency or consistency e. Disease-Related Concerns Allergies Use with caution in patients with significant allergies or a history of asthma Gastrointestinal Disease Use with caution in patients with a history of GI disease, particularly colitis Hepatic Impairment Use with caution in patients with moderate to severe liver disease since half-life may be prolonged However, when administered at everyhour intervals, drug accumulation is rare Monitor hepatic enzymes periodically as dosage adjustments may be necessary for patients with severe liver disease Renal Impairment Lincomycin only Use with caution in patients with renal impairment since the half-life may be prolonged Dosage adjustment may be necessary with severe impairment.
Concerns Related to Special Populations Atopic patients Use with caution in atopic patients Elderly A subgroup of older patients with associated severe illness may tolerate diarrhea less well Monitor carefully for changes in bowel frequency and consistency. Concerns Related to Adverse Reactions Colitis Clostridium difficile—associated diarrhea CDAD has been reported using nearly all antibacterial agents, including clindamycin and lincomycin, and may range in severity from mild diarrhea to fatal colitis.
Oxygen and IV corticosteroids should also be administered as indicated Superinfection Use may result in the overgrowth of nonsusceptible organisms, particularly yeast Should superinfection occur, appropriate measures should be taken as indicated by the clinical situation. Indications and Use NIH, w, v. Microbiology Streptogramins have antibacterial activity against susceptible organisms such as: Gram-positive bacteria: Enterococcus faecium including: Ampicillin-resistant Enterococcus faecium Multi-drug resistant Enterococcus faecium Vancomycin-resistant Enterococcus faecium VRE Staphylococcus aureus including: Methicillin-resistant Staphylococcus aureus MRSA Methicillin-susceptible Staphylococcus aureus MSSA Multi-resistant coagulase-negative Staphylococcus aureus Staphylococcus epidermidis including: Methicillin-resistant Staphylococcus epidermidis Streptococcus agalactiae Streptococcus pyogenes.
Off-label Uses Bacteremia caused by MRSA Infective endocarditis caused by MRSA Infective endocarditis caused by multidrug-resistant Enterococcus faecium Intravascular catheter-associated bloodstream infections caused by methicillin-resistant coagulase-negative staphylococci or ampicillin and vancomycin-resistant Enterococcus faecium.
Background biochemistry information on translation is provided. Antibiotics presented include puromycin, aminoglycosides, tetracyclines, chloramphenicol, macrolides, lincosamides, streptogramins oxazolidinones, mupirocins, and peptide deformylase inhibitors. Mechanisms of action of the antibiotics and resistance development against the antibiotics are discussed. Skip to main content. This service is more advanced with JavaScript available. Advertisement Hide. Antibiotics That Inhibit Protein Synthesis.
Authors Authors and affiliations Mrinal K. Chapter First Online: 14 August This process is experimental and the keywords may be updated as the learning algorithm improves. This is a preview of subscription content, log in to check access. Science — CrossRef Google Scholar. Nature — CrossRef Google Scholar.
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