Protein Synthesis Inhibitors PDF

Protein Synthesis Inhibitors Tasneem Smerat 1  Inhibitors of Bacterial Protein Synthesis Targeting the bacterial ribosome, which has components that differ structurally from those of the mammalian cytoplasmic ribosome...

Protein Synthesis Inhibitors Tasneem Smerat 1  Inhibitors of Bacterial Protein Synthesis Targeting the bacterial ribosome, which has components that differ structurally from those of the mammalian cytoplasmic ribosome The bacterial ribosome: – Is smaller (70S) than the mammalian ribosome (80S) – Composed of 50S and30S subunits Mammalian ribosomes – 80S – Composed of 60S and40S subunits). 2 Summary of protein synthesis inhibitors 3  Aminoglycoside They had been the mainstays for treatment of serious infections due to aerobic gram-negative bacilli including Pseudomonas aeruginosa. However, because their use is associated with serious toxicities they have been replaced to some extent by safer antibiotics - such as the third- and fourth-generation cephalosporins, the fluoroquinolones, and the carbapenems. Effective for the majority of aerobic G-negative bacilli, including those that may be multidrug resistant, such as 4 Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp.  Aminoglycoside Amikacin Gentamicin Neomycin Streptomycin Tobramycin 5  Aminoglycoside, MOA Bactericidal (concentration dependent killing, PAE) The antibiotic then binds to the 30S ribosomal subunit prior to ribosome formation – inhibit protein synthesis.This “freezes” the initiation complex and causes translation errors The aminoglycosides synergize with β-lactam antibiotics because β-lactam antibiotics enhances diffusion of the aminoglycosides into the bacterium. 6  Aminoglycoside, MOA Empirical treatment of infections suspected of being due to aerobic gram-negative bacilli, including Pseudomonas aeruginosa. The aminoglycosides are effective only against aerobic organisms because strict anaerobes lack the oxygen- requiring drug transport system. 7  Aminoglycoside, Uses Tularemia Rare lymphoid disease. Pahvant Valley plague, rabbit fever, deer fly fever. Tularemia is acquired during rabbit hunting season by hunters skinning infected animals. Pneumonic tularemia results from infection by the respiratory route or by bacteremic seeding of lungs. Gentamicin is effective in treating this disease. 8  Aminoglycoside, Uses Tularemia 9  Aminoglycoside, Uses Infections due to enterococci Urinary tract infections, Bacteremia, Endocarditis, Intra-abdominal and pelvic infections. Recommended therapy is with gentamicin or streptomycin plus vancomycin or a β-lactam, such as ampicillin. 10  Aminoglycoside, Uses Infections due to pseudomonas aeruginosa Treatment includes tobramycin alone or in combination with an antipseudomonal penicillin, such as piperacillin or ticarcillin. Aminoglycosides may only be used as monotherapy for UTIs. 11  Aminoglycoside, Therapeutic uses Streptomycin is currently used only for: plague (Yersinia pestis) severe cases of brucellosis adjunct to the treatment of recalcitrant mycobacterial Infections Gentamicin & tobramycin are active against Enterobacter, Pseudomonas, Klebsiella, and Serratia spp  Aminoglycoside, Therapeutic uses Amikacin is used in the treatment of severe gram- negative infections, especially those resistant to gentamicin or tobramycin Neomycin is administered: – Topically for minor soft-tissue infections (often in combination with bacitracin and polymyxin) – Orally (neomycin) for hepatic encephalopathy (GI bacteria by-products result in large amounts of ammonia, which is normally cleared by liver; use of neomycin temporarily inactivates the intestinal flora) 13  Aminoglycoside, Therapeutic uses Spectinomycin structurally related to aminoglycosides and is is administered intramuscularly asan ✓ alternative for the treatment of acute gonorrhea ✓ or for gonococci resistant to penicillin ✓ or in patients hypersensitive to penicillin 14  Aminoglycoside, Pharmacokinetics Administration: All aminoglycosides (except neomycin) must be given parenterally ( highly polar ). - Note: The severe nephrotoxicity associated with neomycin precludes parenteral administration - its current use is limited to topical application for skin infections or oral administration to prepare the bowel prior to surgery. 15  Aminoglycoside, Pharmacokinetics Administration: Mainly given as: Once daily dosing (concentration dependent killing + postantibiotic effect) This results in less toxicity, and is less expensive to administer. Elimination All are rapidly excreted into the urine, predominantly by glomerular filtration 16 Accumulation occurs in patients with renal failure and requires dose modification.  Aminoglycoside, side effects Ototoxicity Ototoxicity (vestibular and cochlear) is directly related to high peak plasma levels and the duration of treatment. Deafness may be irreversible and has been known to affect fetuses in uterus. Patients simultaneously receiving another ototoxic drug, such as (cisplatin or the loop diuretics, furosemide, bumetanide, or ethacrynic acid), are particularly at risk. Vertigo and loss of balance (especially in patients receiving streptomycin) may also occur because these drugs affect the vestibular apparatus. 17  Aminoglycoside, side effects Nephrotoxicity This results in kidney damage ranging from mild, reversible renal impairment to severe, acute tubular necrosis, which can be irreversible. Neuromuscular paralysis: Patients with myasthenia gravis are particularly at risk. Prompt administration of calcium gluconate or neostigmine 18 can reverse the block that causes neuromuscular paralysis.  Tetracyclines – Include: Tetracycline, demeclocycline, doxycycline, minocycline – Mechanism of action Tetracyclines concentrate intracellularly in susceptible organisms and binds 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 19  Tetracyclines – Coverage: Gram- negative rods: brucella, vibrion cholera, Yersinia Gram-positive bacilli: bacillus anthracis Spirochetes : borrelia burdoferi Mycoplasma pneumonia Chlamydia species Rickettsia 20 Broad-spectrum bacteriostatic antibiotics 21  Tetracyclines, uses Lyme disease Spirochete infection (Borrelia) transmitted by the bite of the infected ticks Infection: Skin lesions, headache, meningoencephalitis, arthritis. A single, 200 mg dose of doxycycline, given within 72 hours after a tick bite, can prevent development of the disease. 22 Lyme disease 23  Tetracyclines, uses Mycoplasma pneumonia Community acquired pneumonia Treatment with doxycycline leads to a shorter duration of fever, cough, and malaise. Treatment with macrolides is also effective. 24  Tetracyclines, uses Cholera Caused by V. cholerae Fecally contaminated food and water The organism multiplies in the gastrointestinal tract, where it secretes an enterotoxin that produces diarrhea. Treatment includes 25 - doxycycline, which reduces the number of intestinal vibrios - fluid replacement.  Tetracyclines, uses Chlamydial infection Chlamydia trachomatis - Sexually transmitted disease: urethritis, pelvic infammatory disease Chlamydia psittaci - Causes psittacosis, which usually takes the form of pneumonia. 26 Doxycycline or azithromycin is used to treat chlamydial infections.  Tetracyclines, uses Rocky mountain spotted fever Rickettsia rickettsii Fever, chills, ache in bone and joints Response to tetracyclines is prompt if the drug is started early in the disease process. 27  Tetracyclines, uses Acne Antibiotics such as tetracyclines and macrolides (higher resistance than tertacyclines) are the agents of choice for papulopustular acne. Doxycycline (initial dose is 100 or 200 mg daily, followed by 50 mg daily as a maintenance dose after improvement is seen) and Minocycline (100 mg/day or 50 mg twice daily) are commonly used for moderate to severe28 acne vulgaris.  Tetracyclines, uses Eradication of Helicobacter pylori Tetracycline (500 mg four times daily) is one of the drugs in Bismuth-based four-drug regimens Demeclocydine is an ADH antagonists. Used in treatment of syndrome of inappropriate ADH secretion (SIADH). 29  Tetracyclines, side effects Gastric discomfort: Epigastric distress commonly results from irritation of the gastric mucosa Effects on calcified tissues: Deposition in the bone and primary dentition occurs during calcification in growing children. Dr. Samah Al-Jabi 30  Tetracyclines, side effects Phototoxicity: Phototoxicity, such as severe sunburn, occurs when a patient receiving a tetracycline is exposed to sun or ultraviolet. - Least with minocycline Vestibular problems: dizziness, nausea, and vomiting - occur particularly with minocycline, which concentrates in the endolymph of the ear and affects function. Superinfections: Overgrowths of Candida (for example, in the vagina) 31 Resistant staphylococci (in the intestine) may occur. Pseudomembranous colitis due to an overgrowth of Clostridium difficile  Tetracyclines Resistance is plasmid-mediated and results primarily from: – Adecreased ability to accumulate in the bacteria – The production of an inhibitor of the binding site for tetracyclines – Resistance to one tetracycline confers resistance to some, but not all Tetra 32  Tetracyclines, C/I The tetracyclines should not be employed in pregnant or breast-feeding women or in children less than 8 years of age. 33  Tetracyclines Pharmacokinetic properties – Tetracyclines are variably but adequately absorbed from the GI tract; they can also be administered parenterally – Tetracyclines are distributed throughout body fluids – Therapeutic concentrations in the brain and CSF can be achieved with minocycline only – Absorption is impaired by stomach contents, especially milk and antacids 34 Effect of antacids and milk on the absorption of Tetracyclines 35  Tetracyclines Continue…Pharmacokinetic properties – Many tetracyclines undergo enterohepatic recirculation. – The primary route of elimination for most tetracyclines is the kidney. – Doxycycline do not accumulate and hence are the safest tetracycline to administer to individuals with impaired renal function. 36  Glycylcyclines Tigecycline is the first available member Tigecycline, a derivative of minocycline, is structurally similar to the tetracyclines Mechanism of action: – Exhibits bacteriostatic action by reversibly binding to the 30S ribosomal subunit and inhibiting protein translation.  Use: Tigecycline is indicated for treatment of complicated 37 skin and soft tissue infections as well as complicated intra-abdominal infections  Antibacterial spectrum of Tigecycline Tigecycline exhibits expanded broad-spectrum activity that includes – Methicillin-resistant staphylococci (MRSA) – Multidrug-resistant Streptococcus pneumoniae – Other susceptible strains of streptococcalspecies – Vancomycin-resistant enterococci (VRE) – Extended-spectrum b-lactamase producing gram- negative bacteria – Acinetobacter baumannii – Many anaerobic organisms Tigecycline is not active againstPseudomonas species 38  Tigecycline Resistance: Tigecycline was developed to overcome the recent emergence of tetracycline class resistant organisms Adverse effects Tigecycline is well tolerated, with the main adverse effects being similar to those of the tetracycline class The most commonly reported-class adverse effects were nausea and vomiting Drug interactions It has been found to inhibit the clearance of Warfarin. Therefore, it is recommended that anticoagulation be monitored closely when tigecycline is coadministered 39 with warfarin.  MACROLIDES & Ketolids Chemistry – Erythromycin is a natural product of Streptomyces erythreus – Clarithromycin and azithromycin are semi- synthetic derivatives – Structurally, drugs are quite big (14 to 15 member lactone ring attached to one or more deoxy sugars Erythromycin 40  MACROLIDES & Ketolids Mechanism(s) of action of Macrolides – In general, bacteristatic (can be bactericidal in high concentrations against susceptible bacteria) – Inhibits protein synthesis by binding irreversibly to the bacterial 50S ribosomal subunit. – It inhibits aminoacyl translocation 41 and the formation of initiation complexes Typical therapeutic applications of macrolides 42  Pharmacokinetics of Macrolides – Administered orally & absorbed in upper small intestine – Gastric acid inactivates the drug & therefore, pills are coated to survive stomach acid – Food delays absorption for erythromycin and azithromycin – Readily diffuses in all intracellular fluids except CSF and brain 43  Macrolides Erythromycin – Esters of erythromycin (stearate, estolate, ethylsuccinate) provide improved acid stability – Higher concentrations available if givenIV – Effective against many of the same organisms as penicillin G , therefore, it may be used in patients who are allergic to the penicillins. Clarithromycin – Slightly more effective against staph and strep than erythromycin 44 – Can be given with food  Macrolides Azithromycin – Slightly less effective against G+ – Works better than other two macrolides against Haemophilus influenzae – Works great against atypical mycobacteria – Azithromycin is far more active against respiratory infections due to H. influenzae and Moraxella catarrhalis. 45 – Azithromycin is now the preferred therapy for urethritis caused by Chlamydia trachomatis.  Macrolides Telithromycin – The only ketolide in the market at this moment – Antibacterial spectrum: similar to that of Azithromycin. – ketolides are effective against macrolide-resistant bacteria, due to: Their ability to bind at two sites at the bacterial ribosome Have a structural modification that makes them poor substrates for efflux-pump mediated resistance 46 Some properties of the Macrolide antibiotics 47  Therapeutic Uses of Macrolides Mycoplasma infections Legionnaires’ disease Chlamydia infections – Safe alternative to tetracyclines in pregnant women with STDs Effective against pneumonia Diphtheria and pertussis Staph and strep infections – safe alternative for patients 48 sensitive to beta- lactams  Therapeutic Uses of Macrolides Gastrointestinal infections – Campylobacter gastroenteritis – Helicobacter pylori infections.Erythromycin in concentrations of 1% to 4% (applied twice daily) with or without zinc is effective against inflammatory acne. - Zinc combination products may enhance penetration of erythromycin into the pilosebaceous unit. Tetanus 49 AIDs related infection – Atypical mycobacterial infections – Toxoplasmosis encephalitis – Cryptosporidiun diarrhea  Macrolides TOXICITY Epigastric distress with large doses of erythromycin Cholestatic hepatitis with estolate ester of erythromycin (rare) Ototoxicity 50  Macrolides Drug intraction Erythromycin and Clarithromycin inhibit CYP3A4 metabolismand thereby potentiate the effects of: Carbamazepine Corticosteroids Cyclosporine Digoxin Ergot alkaloids Theophylline Triazolam Valproate Warfarin 51  Others Fidaxomicin Chloramphenicol Clindamycin Streptogramins(dalfopristin/quinupristin) Linezolid 52  Fidaxomicin Macrocyclic antibiotic with a structure similar to the macrolides 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 susceptibleorganisms 53  Fidaxomicin Has a very narrow spectrum of activity limited to gram- positive aerobes and anaerobes Active against staphylococci and enterococci, but primarily used against Clostridium difficile (bactericidal) Has minimal systemic absorption and primarily remains within the GIT, thus ideal for the treatment of C. difficile infection 54  Chloramphenicol Chemistry – Produced by Streptomyces vnezuelae – Unique in that it contains a nitrobenzene moiety Spectrum of coverage – broad Mechanism(s) of action – Reversibly binds to ribosome – Bacteriostatic 55  Chloramphenicol Chloramphenicol Mechanisms of resistance – Aacetylation of drug prevents it from binding to ribosome – Efflux – Mutations in the ribosome 56  Chloramphenicol Pharmacokinetics – Rapidly absorbed from the GI tract when givenorally – May also be given parenterally as a prodrug sodium succinate salt – Readily penetrates CNS, with or without inflammation – Prodrug is rapidly excreted by the kidneys & dosage should be adjusted in patients with hepatic failure, not necessarily renal failure 57 Chloramphenicol 58  Chloramphenicol Therapeutic Uses (a “second choice” drug) – Typhoid fever (Salmonella enterica) – Bacterial meningitis – Anaerobic infections – Rickettsial disease 59  Chloramphenicol (Toxicity/Contraindications) Hypersensitivity reactions Hematological toxicity – Dose related toxicity that presents as anemia & Aplastic anemia Hemolytic anemia occurs in patients with low levels of glucose 6-phosphate dehydrogenase. Aplastic anemia: which although rare is idiosyncratic and usually fatal. Nausea, vomiting, nasty taste, and diarrhea following 60 oral dose  Chloramphenicol (Toxicity/Contraindications) Gray baby syndrome – Therefore, neonates have a decreased ability to excrete the drug (low capacity to glucuronylated the antibiotic), which accumulates to levels that interfere with the function of mitochondrial ribosomes. – This leads to poor feeding, depressed breathing, cardiovascular collapse, cyanosis, and death. – Death occurs in 40% of patients 61  Chloramphenicol (Toxicity/Contraindications) Drug interactions – Prolongs half-lives of drugs that use cytochrome P450 isozymepathway for metabolism – This includes drugs such as warfarin, and anti-retroviralprotease inhibitors 63  Clindamycin Spectrum of coverage – Similar to Macrolides – Particularly effective against anaerobes (Bacteroides) Mechanism of action: same as Macrolides 64  Clindamycin Mechanism(s) of resistance – Ribosomal methylation – Altered metabolism Absorbance – Nearly all is absorbed after oral administration – Food does not interfere with absorption – Can also be given parenterally or topically 65  Clindamycin Therapeutic Uses – Anaerobic infections (dental, resp & peritonial) except brain abscesses – Staphylococcal infections Toxicity/Contraindications – Diarrhea (common) – Pseudomembranous colitis due to overgrowth of toxin- producing Clostridium difficile (uncommon) – Skin rash (uncommon to common) – SJSsyndrome, granulocytopenia, thrombocytopenia, anaphylaxis (rare) 66 Clindamycin 67  Streptogramins Two streptogramins in one drug:  Streptogramin A (Dalfopristin), streptogramin B (Quinupristin)  Synercid – a 30:70 mix of streptogramins A and B Mechanism of action – same as the macrolides, bind to 50S ribosomal subunit and prevent protein synthesis Mechanism of resistance – same as macrolides 68  Streptogramins Administration &Pharmacokinetics  Only given IV over 1 hour  Incompatible with saline and heparin  Administered with 5% dextrose in water  The half-life is less than 1 hour  Hepatic metabolism with 80% eliminated by biliary excretion & the remaining 20% is by kidney  They are inhibitors for CYP450 69  Streptogramins Spectrum of coverage: G+ cocci Therapeutic Uses  Treatment of vancomycin-resistantenterococci (VRE)  Treatment of methicillin-sensitive staph and strep skin infections 70  Streptogramins Toxicity/Contraindications – Infusion-related events (common): Pain and phlebitis at infusion site – Arthralgias and myalgias in patients with liver problems (accumulation of metabolites) 71  Linezolid Spectrum of coverage  G+ only Not effective against anaerobes 72  Linezolid Mechanism(s) of action – similar to macrolides Mechanism(s) of resistance – ribosomal mutation 73  Linezolid Absorbance – Oral or IV administration results in 100% absorbance – Food does not interfere with oral absorption Excretion – Excreted mainly by kidney – Remainder is excreted by liver 74  Linezolid Therapeutic Uses: – Treatment of vancomycin-resistant enterococci(VRE) – Treatment of methicillin-sensitive S. aureus and MRSA Toxicity/Contraindications – Minor gastrointestinal complaints (common) – Myelosuppression (uncommon) 75 Bactericidal vs. Bacteriostatic 76 Nucleic Acid Synthesis Inhibitors Tasneem Smerat  Fluroquinolones,, MOA Once inside the cell, they inhibit the replication of bacterial DNA by interfering with the action of DNA gyrase (topoisomerase II) and topoisomerase IV during bacterial growth and reproduction. Inhibition of DNA gyrase prevents relaxation of supercoiled DNA, promoting DNA strand breakage. Inhibition of topoisomerase IV impacts chromosomal stabilization during cell division, thus interfering with the separation of newly replicated DNA.  Fluroquinolones,, Antimicrobial spectrum Fluoroquinolones are bactericidal They exhibit concentration dependent killing. Bactericidal activity is more pronounced as serum drug concentrations increase to approximately 30-fold the MIC of the bacteria. In general, they are effective against - Gram negative organisms such as - Enterobacteriaceae - Pseudomonas - Haemophilus influenzae -Moraxella catarrhalis - Legionellaceae - Chlamydia - Mycoplasma - Some Mycobacteria. - Gonorrhea.  Fluroquinolones,, Generations The newer agents (for example, levofloxacin and moxifloxacin) also have good activity against - some gram-positive organisms, such as: Streptococcus pneumoniae. - Moxifloxacin has activity against many anaerobes. First generation: - Nalidixic acid - A narrow spectrum of susceptible organisms usually confined to the urinary tract. Second generation - Ex: Ciprofloxacin, norfloxacin, ofloxacin -They are active against aerobic gram-negative - Atypical bacteria (Chlamydia, mycoplasma). Third generation - Levofloxacin - It has increased activity against gram-positive bacteria. Fourth generation - Moxifloxacin - It has increased activity against anaerobic, as well as, gram-positive organisms.  Fluroquinolones,, Uses Ciprofloxacin Traveler’s diarrhea caused by E. coli. It is the most potent of the fluoroquinolones for Pseudomonas aeruginosa infections (treatment of pseudomonal infections associated with cystic fibrosis) Is also of benefit in treating resistant tuberculosis. Ciprofloxacin is also commonly used to treat typhoid fever in third- world countries. Norfloxacin Effective against both gram-negative (including P. aeruginosa) and gram-positive organisms. Used in treating complicated and uncomplicated UTIs, prostatitis, and traveler's diarrhea (unlabeled use). Levofloxacin Levofloxacin is an isomer of ofloxacin and has largely replaced it clinically. It can be used in the treatment of prostatitis due to E. coli and of sexually transmitted diseases, with the exception of syphilis. It may be used as alternative therapy in patients with gonorrhea. Levofloxacin Additionally, due to its broad spectrum of activity, levofloxacin is utilized in a wide range of infections: - skin infections - acute sinusitis - acute exacerbation of chronic bronchitis - community-acquired pneumonia - nosocomial pneumonia. Levofloxacin has excellent activity against S. pneumoniae respiratory infections Moxifloxacin Has enhanced activity against gram-positive organisms (for example, S. pneumoniae). Has excellent activity against many anaerobes. It has very poor activity against P. aeruginosa. Moxifloxacin does not concentrate in urine and is not indicated for the treatment of UTIs. Enterotoxigenic (cholera-like) diarrhea Ciprofloxacin : 500 mg orally twice daily × 3 days Norfloxacin: 400 mg orally twice daily × 3 days Invasive (dysentery-like) diarrhea -- Salmonella norfloxacin 400 mg, or ciprofloxacin 500 mg twice daily × 5 days Acute Respiratory Exacerbations in Chronic Bronchitis Ciprofloxacin 500–750 mg X 2 Levofloxacin 500–750 mg X 1 Moxifloxacin 400 mg X 1 Bacterial Pneumonia Levofloxacin 500–750 mg X 1 Ciprofloxacin 500–1500 mg X 2 Uncomplicated UTI Ciprofloxacin 250 mg Twice a day for 3 days Norfloxacin 400 mg Twice a day for 3 days Levofloxacin 250 mg Once a day for 3 days Complicated UTI Norfloxacin 400 mg Twice a day 7–10 days Ciprofloxacin 250–500 mg Twice a day 7–10 days Levofloxacin 250 mg Once a day 7–10 days Acute pyelonephritis Ciprofloxacin 500 mg Twice a day 14 days Levofloxacin 250 mg Once a day 14 days  Fluroquinolones,, Pharmacokinatics Absorption Only 35 to 70% of orally administered norfloxacin is absorbed, compared with 85 to 95 percent of the other fluoroquinolones. Intravenous preparations of ciprofloxacin and levofloxacin are available. The fluoroquinolones with the longest half-lives (levofloxacin and moxifloxacin) permit once-daily dosing. Absorption Ingestion of the fluoroquinolones with sucralfate, antacids containing aluminum or magnesium, or dietary supplements containing iron or zinc can interfere with the absorption of these antibacterial drugs. Calcium and other divalent cations have also been shown to interfere with the absorption of these agents. Elimination: Most fluoroquinolones are excreted renally, therefore, the dose needs to be adjusted when renal function changes. Moxifloxacin, is excreted primarily by the liver, and no dose adjustment is required with decreased renal functioning.  Fluroquinolones,, adverse effects Gastrointestinal: - The most common adverse effects of the fluoroquinolones (3-6%) - nausea, vomiting, and diarrhea. Central nervous system problems: - headache and dizziness or light- headedness. - Thus, patients with CNS disorders, such as epilepsy, should be treated cautiously with these drugs. Phototoxicity: - Patients taking fluoroquinolones are advised to avoid excessive sunlight and to apply sunscreens. - It is advisable that the drug should be discontinued at the first sign of phototoxicity. Connective tissue problems: - Fluoroquinolones should be avoided in pregnancy, in nursing mothers, and in children under 18 years of age Connective tissue problems: - Fluoroquinolones should be avoided in pregnancy, in nursing mothers, and in children under 18 years of age Moxifloxacin and other fluoroquinolones, may prolong the QTc interval. should not be used in patients who are predisposed to arrhythmias or are taking antiarrhythmic medications and not being actively monitored.  Fluroquinolones,, DI Complexation: The effect of antacids and cations on the absorption. Ciprofloxacin and ofloxacin: - CYP inhibitors - can increase the serum levels of theophylline, warfarin, caffeine, and cyclosporine by inhibiting their metabolism. - This is not the case with the third- and fourth-generation fluoroquinolones  Urinary tract antiseptics/antimicrobials Urinary tract infections - most commonly uncomplicated acute cystitis “urinary bladder inflammation” and pyelonephritis “ascending UTI that has reached the pelvis of the kidney) - occur in women of child-bearing age and in the elderly. Escherichia coli is the most common pathogen, causing about 80 percent of uncomplicated upper and lower UTIs. Staphylococcus saprophyticus: second most common Other common causes including: Klebsiella pneumoniae , Proteus mirabilis These infections may be treated with any one of a group of agents called urinary tract antiseptics, including: Methenamine Nitrofurantoin Nalidixic acid. These drugs do not achieve antibacterial levels in the circulation, but because they are concentrated in the urine  Methenamine Decomposes at an acidic pH of 5.5 or less in the urine producing formaldehyde, which is toxic to most bacteria. The reaction is slow, requiring 3 hours to reach 90 percent decomposition. Methenamine should not be used in patients with indwelling catheters. Bacteria do not develop resistance to formaldehyde. Urea-splitting bacteria that alkalinize the urine, such as Proteus species, are usually resistant to the action of methenamine. Methenamine is used to treat lower UTIs but is not effective in upper UTIs. Because the liver rapidly metabolizes ammonia to form urea, methenamine is contraindicated in patients with hepatic insufficiency, in which elevated levels of circulating ammonium ions would be toxic to the CNS.  Nitrofurantoin Nitrofurantoin sensitive bacteria reduce the drug to a highly active intermediate that inhibits various enzymes and damages bacterial DNA. Antibiotic activity is greater in acidic urine. It is useful against E. coli. Gram-positive cocci are susceptible. Bacteria that are susceptible rarely become resistant during therapy. Hemolytic anemia is encountered in patients with G6PD def. This medicine can turn urine a dark yellow or brown colour. Contraindications: Anuria, oliguria, significant impairment of renal function, pregnancy at term or ≥ 38 weeks pregnant. Adverse effects include: gastrointestinal disturbances acute pneumonitis neurologic problems. Metabolic enzymes inhibitors 10 5 Bacteriostatic in most tissues, can be cidal in urine The sulfonamides (sulfa drugs) are a family of antibiotics that inhibit this de novo synthesis of folate. Trimethoprim: a folate antagonist - prevents microorganisms from converting dihydrofolic acid to tetrahydrofolic acid, with minimal effect on a human cell’s ability to make this conversion.  Folate antagonist Thus, both sulfonamides and trimethoprim interfere with the ability of an infecting bacterium to divide. Cotrimoxazole: - is a combination of the sulfonamide, sulfamethoxazole, with trimethoprim - provides a synergistic combination that is used as effective treatment of a variety of bacterial infections. itis widely used to treat: UTI respiratory tract infections gastrointestinal infections pneumocystis infections Folate Antagonists  Folate antagonist Inhibitors of folate synthesis Mafenide Silver sulfadiazine Sulfacetamide Sulfamethoxazole Sulfasalazine Sulfisoxazole Inhibitors of folate reduction Pyrimethamine Trimethoprim Combination of inhibitors of folate synthesis and reduction Cotrimoxazole (trimethoprim + sulfamethoxazole). Sulfadiazine + pyrimethamine  CO-TRIMOXAZOLE (Bactrim) The combination of trimethoprim with sulfamethoxazole, called co-trimoxazole Shows greater antimicrobial activity than equivalent quantities of either drug used alone (synergism). The combination was selected because of their synergistic activity and the similarity in the half-lives of the two drugs.  CO-TRIMOXAZOLE (Bactrim) A broader spectrum than the sulfa drugs. It is effective in treating: UTIs Respiratory tract infections Pneumocystis jiroveci pneumonia Ampicillin- or chloramphenicol-resistant systemic salmonella infections. Community acquired skin and soft tissue infections caused by MRSA Nocardia species: a severe pulmonary infection in immunocompromised hosts.  Sulfonamide uses Main Sulfa Preparations Sulfamethoxazole + trimethoprim = UTI (treatment and prophylaxis in recurrent infection), ear infections, gonorrhea Sulfasoxazole+ erythromycin = otitis media Sulfasalazin (sulfapyridine and 5-aminosalicylate) = chronic inflammatory bowel disease Silver sulfadiazine, mefanide = burns & wounds Sulfacetamide = wounds, trachoma Sulfadiazine + pyrimethamine: Toxoplasmosis Sulfamethoxazole + trimethoprim Acute pyelonephritis 1 DS tablet Twice a day (14 days). Lower urinary tract Infections (Uncomplicated) 2 DS tablets Single dose (1 day) 1 DS tablet Twice a day (3 days) Lower urinary tract Infections (Complicated): 1 DS tablet Twice a day 7–10 days  Sulfonamide administration After oral administration, most sulfa drugs are well absorbed via the small intestine An exception is sulfasalazine. - It is not absorbed when administered orally or as a suppository. - treatment of is reserved for treatment of chronic inflammatory bowel disease (for example, Crohn's disease or ulcerative colitis). Intravenous sulfonamides are generally reserved for patients who are unable to take oral preparations. Topical: silver sulfadiazine or mafenide == burn and wound Sulfacetamide is used to treat ophthalmic infections Very high aqueous concentrations are not irritating (pH 7.4) Very good penetration into ocular tissue  Sulfonamide adverse effects Hemopoietic disturbances: Hemolytic anemia is encountered in patients with glucose 6- phosphate dehydrogenase deficiency. Agranulocytosis Aplastic anemia  Crystalluria: Nephrotoxicity develops as a result of crystalluria. Adequate hydration and alkalinization of urine prevent the problem by reducing the concentration of drug and promoting its ionization. Hypersensitivity Kernicterus (newborns) Displacement of bilirubin from plasma albumin Bilirubin deposits in brain, causing an encephalopathy Bilirubin deposits in neonatal brain this is why sulfonamides are not given to pregnant or lactating women!