Broad spectrum antibiotics
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Tetracyclines and chloramphenicol are broad-spectrum antibiotics that act by inhibiting bacterial protein synthesis. Tetracyclines are bacteriostatic and include doxycycline and minocycline. They are used for respiratory, skin, and sexually transmitted infections. Adverse effects include gastrointestinal issues and photosensitivity. Chloramphenicol is bacteriostatic and used for serious infections but can cause fatal blood disorders so is reserved for life-threatening infections when safer alternatives cannot be used.
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Broad spectrum antibiotics
- 2. Classification On Basis Of Mech 1. bacteriostatic protein synthesis inhibitors that target the ribosome, such as tetracyclines, macrolides, lincosamides, streptogramins (quinupristin/ dalfopristin), and oxazolidinones (linezolid); 2. bactericidal agents acting on the cell wall or cell membrane, such as polymyxins, glycopeptides (vancomycin)and lipopeptides (daptomycin); 3. miscellaneous agents acting by diverse mechanisms, such as metronidazole, bacitracin, and mupirocin.
- 4. Tetracyclines • derivatives of a basic four-ring structure • Demeclocycline, tetracycline, minocycline, doxycycline available in the U.S. for systemic use. • Glycylcyclines are tetracycline congers; broad- spectrum activity and activity against tetracycline- resistant bacteria; • the currently available glycylcycline is tigecycline.
- 6. Antimicrobial Spectrum • Bacteriostatic, intrinsically more active against gram-positive than gram-negative. • Streptococcus pyogenes and penicillin-susceptible Streptococcus pneumoniae, MSSA and MRSA. Bacillus anthracis and Listeria monocytogenes. Haemophilus influenzae , Burkholderia pseudomallei . Brucella . Haemophilus ducreyi (chancroid), Vibrio cholerae, and Vibrio vulnificus and inhibit the growth of Campylobacter jejuni, Helicobacter pylori, Yersinia pestis, Yersinia enterocolitica,Francisella tularensis, and Pasteurella multocida. • alternative agents for actinomycosis.
- 7. Antimicrobial Spectrum • Rickettsia, Coxiella burnetii, Mycoplasma pneumoniae, Chlamydia spp., Legionella spp., Ureaplasma, some atypical mycobacteria, and Plasmodium sp, spirochetes, Borrelia recurrentis, Borrelia burgdorferi (Lyme disease), Treponema pallidum (syphilis), and Treponema pertenue. • tigecycline greater activity against enterococci, Enterobacteriaceae, Acinetobacter, and Bacteroides fragilis: tigecycline lacks activity against Pseudomonas, Proteus, and Providencia sp.
- 8. Resistance plasmid mediated and often inducible. • Decreased accumulation of tetracycline as a result of either decreased antibiotic influx or acquisition of an energy-dependent efflux pathway • Production of a ribosomal protection protein that displaces tetracycline from its target • Enzymatic inactivation of tetracyclines
- 9. Resistance • The glycylamido moiety characteristic of tigecycline reduces its affinity for most efflux pumps, restoring activity against many organisms displaying tetracycline resistance due to this mechanism. • Binding of glycylcyclines to ribosomes is also enhanced, improving activity against organisms that harbor ribosomal protection proteins that confer resistance to other tetracyclines.
- 10. ADME • Oral absorption incomplete. • Tigecycline only for parenteral administration. • Concurrent ingestion of divalent and trivalent cations (e.g., Ca2+, Mg2+, Al3+, Fe2+/3+, and Zn2+) impairs absorption. Thus, dairy products, antacids, aluminum hydroxide gels; calcium, magnesium, and iron or zinc salts; bismuth subsalicylate and dietary iron and zinc supplements can interfere with absorption of tetracyclines. • Demeclocycline incompletely absorbed; t1/2 of 16 h.
- 11. ADME • distribute throughout the body, urine and prostate. accumulate in reticuloendothelial cells and in bone, dentine, and enamel of unerupted teeth. • Tigecycline high Vd 7–10 L/kg; into the CSF. cross the placenta and found in breast milk. • eliminated primarily by the kidney, tigecycline, doxycycline minocycline is extensively metabolized by the liver before excretion
- 12. USES • Respiratory Tract Infections;Doxycycline has good activity against Streptococcus pneumoniae and H. influenzae and excellent activity against atypical pathogens such as Mycoplasma and Chlamydophila pneumoniae. • Tigecycline is effective for use as a single agent for adults hospitalized with community-acquired bacterial pneumonia.
- 13. USES • Tigecycline approved for complicated skin and soft-tissue infections. • Doxycycline and minocycline good activity against staphylococci and cutaneous MRSA infections. • Low doses of tetracycline; acne (25 mg orally twice a day).
- 14. USES • Intra-abdominal Infections. • tigecycline possesses excellent activity against these pathogens as well as Enterococcus.
- 15. USES • STD. A 7-day treatment course of doxycycline is as effective as, but less convenient than, singledose azithromycin in the treatment of uncomplicated genital infections due to Chlamydia trachomatis. Chlamydia trachomatis is coexistent pathogen in acute PID, and doxycycline combination therapy regimens • Acute epididymitis caused by C. trachomatis or Neisseria gonorrhoeae in men <35 years of age. Regimens; single injection of ceftriaxone (250 mg), doxycycline for 10 days. Sexual partners should be treated. • Doxycycline for 21 days 1st -line therapy for treatment of LGV
- 16. USES • lifesaving in rickettsial infections, including Rocky Mountain spotted fever, recrudescent epidemic typhus (Brill disease), murine typhus, scrub typhus, rickettsialpox, and Q fever.
- 17. USES • Doxycycline is indicated for prevention or treatment of anthrax. • It should be used in combination with another agent when treating inhalational or GI infection. • recommended duration of therapy is 60 days for bioterrorism exposures.
- 18. USES • Except for local use in the eye, topical use of the tetracyclines is not recommended, • although they are FDA-approved as over-the-counter topical first-aid antibiotics. • Sustained-release preparations of minocycline and doxycycline for subgingival administration are used in dentistry.
- 19. USES • Other Infections. combination with rifampin or streptomycin effective for acute and chronic infections; Brucella melitensis, Brucella suis, Brucella abortus. • (streptomycin preferable) tetracyclines in tularemia. Actinomycosis;(penicillin G), treated with a tetracycline. Minocycline alternative for treatment of nocardiosis, but a sulfonamide should be used concurrently. Yaws and relapsing fever • in acute treatment and prophylaxis leptospirosis, Borrelia recurrentis (relapsing fever) and B. burgdorferi (Lyme disease), susceptible atypical mycobacteria Mycobacterium marinum.with bismuth and metronidazole used for H. pylori .
- 20. Adverse Effects • Gastrointestinal irritation, after oral administration. Epigastric burning and distress, abdominal discomfort, nausea, vomiting, and diarrhea. • esophagitis and esophageal ulcers; • patients should take oral formulations with a full glass of water while standing. • Tigecycline IV nausea and vomiting
- 21. Adverse Effects Photosensitivity. • Demeclocycline, doxycycline, and other tetracyclines and, to a lesser extent, glycylcyclines • Onycholysis and pigmentation of the nails
- 22. Adverse Effects Hepatic Toxicity. • in patients with renal failure receiving 2 g or more of tetracycline per day parenterally, • also may occur when large quantities orally.
- 23. Adverse Effects • Renal Toxicity. aggravate azotemia in patients with renal disease. Doxycycline, minocycline, and tigecycline have fewer renal side effects than other tetracyclines. Nephrogenic diabetes insipidus has been observed in some patients receiving demeclocycline, and this phenomenon has been exploited for the treatment of SIADH • Fanconi syndrome (nausea, vomiting, polyuria, polydipsia, proteinuria, acidosis, glycosuria, aminoaciduria) outdated tetracycline, due to toxic effects on the proximal renal tubules.
- 24. Adverse Effects • Effects on Teeth. Children treated develop permanent brown discoloration of the teeth. • The risk is highest when given to infants before the first dentition but may develop if the drug is given between the ages of 2 months and 5 years when these teeth are being calcified. • Treatment of pregnant patients may produce discoloration of the teeth in their children.
- 25. Adverse Effects • deposited in skeleton during gestation, childhood and depress bone growth in premature infants. reversible if short period of exposure. Thrombophlebitis.used in malignant pleural effusions. • Long-term therapy; leukocytosis, atypical lymphocytes, toxic granulation of granulocytes, and thrombocytopenic purpura. cause increased intracranial pressure (pseudotumor cerebri) in young infants, in therapeutic doses. • minocycline; vestibular toxicity, dizziness, ataxia, nausea, and vomiting. >1st dose and disappear within 24–48 h after drug cessation.
- 26. Drug Interactions • oral coadministration of tetracyclines and divalent and trivalent cations can lead to chelation of the tetracycline, with resultant poor absorption. • between doxycycline and hepatic enzyme-inducing agents such as phenytoin and rifampin, but not for minocycline or tigecycline.
- 27. Chloramphenicol • antibiotic produced by Streptomyces venezuelae • introduced in 1948. • can cause serious and fatal blood dyscrasias; • reserve drug for treatment of life-threatening infections (e.g., meningitis, rickettsial infections) in patients who cannot take safer alternatives because of resistance or allergies
- 30. Antimicrobial Spectrum • bacteriostatic,bactericidal against H. influenzae, Neisseria meningitidis, and S. pneumoniae. • some isolates of highly resistant MRSA. enterococci, multidrug- resistant E. faecium.Mycoplasma, Chlamydia, and Rickettsia. Enterobacteriaceae,Strains of V. cholerae
- 31. Resistance • plasmid-encoded acetyltransferase that inactivates the drug. Resistance also can result from decreased permeability and from ribosomal mutation. • Acetylated derivatives of chloramphenicol fail to bind to bacterial ribosomes.
- 32. ADME • available in oral, IV , and topical (e.g., ophthalmic) preparations. widely distributed in body fluids and in CSF. in bile, milk, and placental fluid. • Hepatic metabolism to the inactive glucuronide is the major route of elimination. This metabolite and chloramphenicol are excreted in the urine. Patients with impaired hepatic function have decreased metabolic clearance, and dosage should be adjusted. • bound to plasma proteins; reduced in cirrhotic patients and in neonates
- 33. Uses Typhoid Fever. • Third-generation cephalosporins and quinolones; • less toxic
- 34. Uses Bacterial Meningitis. • H. influenzae, N. meningitidis, • S. pneumoniae in patients allergic to β-lactams and in developing countries.
- 35. Uses • Rickettsial Diseases preferred agents for it. • Rocky Mountain spotted fever, epidemic, murine, scrub, and recrudescent typhus and Q fever • in patients allergic to these drugs, in pregnant women, and in children < 8 years ; prolonged or repeated courses of therapy, chloramphenicol as alternative therapy.
- 36. Adverse Effects • inhibits the synthesis of proteins of the inner mitochondrial membrane, probably by inhibiting the ribosomal peptidyltransferase. • These include subunits of cytochrome c oxidase, ubiquinone- cytochrome c reductase, and the proton-translocating ATPase critical for aerobic metabolism.
- 37. Adverse Effects Hypersensitivity Reactions. Skin rashes • Fever Angioedema . • Jarisch-Herxheimer reactions during treatment of syphilis, brucellosis, and typhoid fever.
- 38. Adverse Effects • Hematological Toxicity a dose-related toxicity; anemia, leukopenia, or thrombocytopenia and aplastic anemia, fatal pancytopenia. • Bone marrow suppression occurs regularly when plasma concentrations are 25 μg/mL or greater and large doses, prolonged treatment, Dose-related suppression of the bone marrow may progress to fatal aplasia • Pancytopenia prolonged therapy ;low incidence, fatality rate is high when bone marrow aplasia is complete, and acute leukemia in who recover. Aplastic anemia (70%) hypoplastic anemia, agranulocytosis, and thrombocytopenia .
- 39. Adverse Effects Other Toxic and Irritative Effects. • Nausea and vomiting, unpleasant taste, diarrhea, and perineal irritation. Blurring of vision, digital paresthesias . • Premature Neonates, gray baby syndrome. begins 2–9 days. Within the first 24 h, vomiting, refusal to suck, irregular and rapid respiration, abdominal distention, periods of cyanosis, and passage of loose green stools occur. Over 24 h, neonates turn ashen-gray, flaccid and hypothermic.
- 40. Drug Interactions • inhibits hepatic CYPs; prolongs the half-lives of drugs that are metabolized by this system. • Concurrent administration of phenobarbital or rifampin, induce CYPs, shortens the t1/2 of the antibiotic
Editor's Notes
- The messenger RNA (mRNA) attaches to the 30S ribosome. The initiation complex of mRNA starts protein synthesis and polysome formation. The nacent peptide chain is attached to the peptidyl (P) site of the 50S ribosome. The next amino acid (a) is transported to the acceptor (A) site of the ribosome by its specific tRNA which is complementary to the base sequence of the next mRNA codon (C). The nascent peptide chain is transferred to the newly attached amino acid by peptide bond formation. The elongated peptide chain is shifted back from the ‘A’ to the ‘P’ site and the ribosome moves along the mRNA to expose the next codon for amino acid attachment. Finally the process is terminated by the termination complex and the protein is released. (1) Aminoglycosides bind to several sites at 30S and 50S subunits as well as to their interface—freeze initiation, interfere with polysome formation and cause misreading of mRNA code. (2) Tetracyclines bind to 30S ribosome and inhibit aminoacyl tRNA attachment to the ‘A’ site. (3) Chloramphenicol binds to 50S subunit—interferes with peptide bond formation and transfer of peptide chain from ‘P’ site. (4) Erythromycin and clindamycin also bind to 50S ribosome and hinder translocation of the elongated peptide chain back from ‘A’ site to ‘P’ site and the ribosome does not move along the mRNA to expose the next codon. Peptide synthesis may be prematurely terminated.
- Inhibition of bacterial protein synthesis by tetracyclines. mRNA attaches to the 30S subunit of bacterial ribosomal RNA. The P (peptidyl) site of the 50S ribosomal RNA subunit contains the nascent polypeptide chain; normally, the aminoacyl tRNA charged with the next amino acid (aa) to be added moves into the A (acceptor) site, with complementary base pairing between the anticodon sequence of tRNA and the codon sequence of mRNA. Tetracyclines bind to the 30S subunit, block tRNA binding to the A site, and thereby inhibit protein synthesis.
- Inhibited practically all types of pathogenic microorganisms except fungi and viruses All gram-positive and gram-negative cocci were originally sensitive, but now Resistance but is common in group B streptococci and penicillin-resistant S. pneumoniae. many Enterobacteriaceae have acquired resistance, Activity against enterococci is limited. , Although all strains of Pseudomonas aeruginosa are resistant Doxycycline and minocycline can be active against some tetracycline- resistant isolates.
- Glycylcyclines (tigecycline) are generally active against organisms that are susceptible to tetracyclines as well as those with acquired resistance to tetracyclines. In particular, There are a few exceptions where other tetracyclines may be more active than tigecycline against certain organisms, such as Stenotrophomonas and Ureaplasma.
- develops slowly in a graded manner.
- Oral doses of doxycycline and minocycline are well absorbed (90%–100%) and have half-lives of 16–18 h; they can be administered at lower doses than tetracycline or demeclocycline. Plasma concentrations are equivalent whether doxycycline is given orally or parenterally. Food, including dairy products, does not interfere with absorption of doxycycline and minocycline.
- Doxycycline is largely excreted unchanged in both the bile and urine reticuloendothelial cells of the liver, spleen, and bone marrow
- Although tetracyclines are broad-spectrum antibiotics, they should be employed only for those infections for which a more selective and less toxic AMA is not available
- Doxycycline no longer is recommended for gonococcal infections because of the spread of resistance (Centers for Disease Control and Prevention, 2015). Nonpregnant penicillin-allergic patients who have primary, secondary, or latent syphilis can be treated with a tetracycline regimen, such as doxycycline for 2 weeks. not used for neurosyphilis.
- Clinical improvement often is evident within 24 h after initiation of therapy. Doxycycline is the drug of choice for treatment of Rocky Mountain spotted fever in adults and in children, including those less than 9 years of age, in whom the risk of staining of permanent teeth is outweighed by the seriousness of this potentially fatal infection.
- Tolerability improved by administering with food, but not be taken with dairy products or antacids.
- may produce photosensitivity reactions in treated individuals exposed to sunlight.
- Pregnant women are particularly susceptible. Doxycycline is probably not associated with hepatotoxicity
- The duration of therapy appears to be less important than the total quantity of antibiotic administered.
- Various skin reactions.angioedema and anaphylaxis; anaphylactoid reactions. Other hypersensitivity reactions are burning of the eyes, cheilosis, atrophic or hypertrophic glossitis, pruritus ani or vulvae, and vaginitis; these reactions can persist for weeks or months after cessation of tetracycline therapy. Cross-sensitization
- Chloramphenicol was initially obtained from Streptomyces venezuelae in 1947. It was soon synthesized chemically and the commercial product now is all synthetic. It is a yellowish white crystalline solid, aqueous solution is quite stable, stands boiling, but needs protection from light. The nitrobenzene moiety of chloramphenicol is probably responsible for the antibacterial activity as well as its intensely bitter taste.
- Inhibition of bacterial protein synthesis by chloramphenicol. Chloramphenicol binds to the 50S ribosomal subunit at the peptidyltransferase site, inhibiting transpeptidation.
- Chloramphenicol binds near the site of action of clindamycin and the macrolide antibiotics. These agents interfere with the binding of chloramphenicol and thus may interfere with each other’s actions if given concurrently.
- , but P. aeruginosa is resistant to even very high concentrations of chloramphenicol. Prevalent strains of Shigella and Salmonella are resistant to multiple drugs, including chloramphenicol. S. aureus tend to be less susceptible
- Poor renal function in the neonate and other states of renal insufficiency result in increased plasma concentrations of chloramphenicol succinate. Decreased esterase activity has been observed in the plasma of neonates and infants, prolonging time to peak concentrations of active chloramphenicol (up to 4 h) and extending the period over which renal clearance of chloramphenicol succinate can occur
- The adult dose of chloramphenicol for typhoid fever is 1 g every 6 h for 4 weeks.
- The total daily dose for children should be 50 mg/kg of body weight, divided into four equal doses given intravenously every 6 h.
- For adults and children with these diseases, a dosage of 50 mg/kg/d divided into 6-h intervals is recommended. For severe or resistant infections, doses up to 100 mg/kg/d may be used for short intervals, but the dose must be reduced to 50 mg/kg/d as soon as possible. Therapy should be continued until the general condition has improved and the patient is afebrile for 24–48 h.
- Two mechanisms apparently are responsible for chloramphenicol toxicity in neonates: (1) a developmental deficiency of glucuronyl transferase, the hepatic enzyme that metabolizes chloramphenicol; and (2) inadequate renal excretion of unconjugated drug. At the onset of the clinical syndrome, chloramphenicol concentrations in plasma usually exceed 100 μg/mL and may be as low as 75 μg/mL.