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Antibiotics Hamzeh Elayan 2015 1 Antibiotics -chemical substances produced by microorganisms such as fungi, actinomycetes and bacteria that suppress the growth of other micro-organisms (Bacteriostatic) or destroy them (Bactericidal) -used to treat bacterial infections. - Ideally, before beginning antibiotic therapy, the causative organism should be identified and sensitivity tests to antibiotics should be determined. 2 Selection of Antimicrobial Agent Empiric therapy - prior to identification of organism in critically ill patients Prophylactic therapy treatment with antibiotics to prevent an infection, as in intra-abdominal surgery Organism’s susceptibility to the antibiotic Patient factors -hypersensitivity, renal/hepatic function, age, pregnancy Effect of site of infection on therapy –blood brain barrier Safety of the agent 3 Cost of therapy Chemotherapeutic Spectra Narrow-spectrum Antibiotics: Act on a single / limited group of micro-organisms; e.g., isoniazid given for mycobacterium Extended-spectrum Antibiotics: Effective against gram-positive organisms and a significant number of gram-negative organisms; e.g., ampicillin Broad-spectrum Antibiotics: Effective against a wide variety of microbial species; e.g., tetracycline & chloramphenicol. Used for infections of unknown origin Can alter the nature of intestinal flora = super infection 4 Combinations of Antimicrobial Drugs Advantages Synergism; the combination is more effective than either drug used separately; betalactams and aminoglycosides Disadvantages Bacteriostatic (tetracycline) drugs may interfere with bactericidal ( penicillin and cephalosporin) drugs 5 Complications of Antibiotic Therapy Resistance – inappropriate use of antibiotics Hypersensitivity – penicillin Direct toxicity – aminoglycosids = ototoxicity Super infections – broad spectrum antimicrobials cause alteration of the normal flora; often difficult to treat. 6 Drug Resistance 1. Alteration of the target site methicillin resistance among Staphylococcus aureus. 2. Enzyme inactivation Some bacteria secrete beta- lactamase enzyme which destroys the beta lactam ring, rendering beta-lactam antibiotics ineffective (penicillins & cephalosporins). Solution - add clavulanic acid - a beta- lactamase inhibitor 3. Active transport of the antibiotic out of the bacterial cell (efflux pumps) tetracyclines, macrolides, & quinolones 7 4. Decreased permeability Alteration in the proteins that form channels in the bacterial cell membrane – Resistance of Pseudomonas aeruginosa to penicillins & cephalosporins Decreased Permeability of the Drug Prevents the drug reaching the target penicillin binding proteins (PBPs) Presence of an Efflux pump also reduces the amount of the intracellular drug 8 Classification of antibiotics according to mechanisms of action. 1. Inhibiton of bacterial cell wall. Penicillin & cephalosporin (structurally similar). Cycloserine, vancomycin 2. Agent affecting cell membrane permeability leading to leakage of intercelluar compounde. Polymyxin, 3. Inhibition of protein synthesis. Chloramphenical, Tetracycline, Erythromycin, Clindamycin, Aminoglycosides. 5. Affecting bacterial nucleic acid metabolism. Rifampin & the quinilones. 6 . Interfering with folate metabolisum. trimethoprim& sulfonamide. 9 Cell wall inhibitors Interfere with synthesis of the bacterial cell wall (mammalians cells do not have it). Cell wall inhibitors require actively proliferating (multiplying) microorganism. The cell wall inhibitors include : Penicillins, Cephalosporins,, Monobactams, Carbepenems, and Vancomycin. 10 Penicillins From mould penicilium notatum Bactericidal The safest & most commonly used. Mechanism: Inhibiting cell wall synthesis. Natural penicillin Benzylpenicillin (Penicillin G) Destroyed by stomach acid. Given IM or IV. Active against: most gram-positive bacteria with the exception of penicillinase-producing S. aureus - most Neisseria species and some gram-negative anaerobes - Not active against most gram-negative aerobic organisms Pinicillin G is inactivated by β-lactamase (Penicillinase). 11 Penicillin G clinical uses Streptococcal infections that include pneumonia, otitis media, meningitis, and septic arthritis. Also effective against: Neisseria meningitidis N. Gonorrhea Clostridium tetani diphtheria syphilis Listeria monocytogenes (anaerobic causes food poisoning) 12 Benzathine penicillin Long acting, IM once every 3–4 weeks A single IM injection of 1.2 million units, is effective treatment for beta–hemolytic streptococcal pharyngitis, it prevents re-infection. Also prophylactic. Prevents reoccurrence of rheumatic fever. Benzathine penicillin G, 2.4 million units IM once a week for 1–3 weeks, is effective in the treatment of syphilis. Also prophylactic. 13 Phenoxymethylpenicillin (Penicillin V) Acid stable, orally active. less potent than penicillin G. Penicillin V often employed in the treatment of oral infection, effective against some anaerobic organism. •Penicillin V is the most frequently prescribed antibiotic for oral infections. It is the first choice in the treatment of odontogenic infections. - post extraction infection - pericoronitis and - salivary gland infection 14 Penicillinase -resistant Penicillins Methcillin (Not available), Oxacillin, Cloxacillin, Narrow spectrum, well-absorbed orally. • Antibacterial spectrum is the same as for penicillin G, but less potent. •Their use is restricted to treatment of infections caused by penicillins -resistant bacteria. Many Staphylococci are now resistant to them. 15 Extended Spectrum Penicillins Ampicillin, fairly well absorbed orally. Amoxicillin, prodrug to ampicillin very well absorbed. Their antibacterial spectrum is the same as for penicillin G plus some Gram-negative bacteria. Most useful antibiotics for treating children suffering from sensitive gram-negative aerobic bacteria, enterococci, and β-lactamase-negative H. influenzae. widely used in the treatment of respiratory infections. Used orally to treat urinary tract infections, sinusitis, otitis, and lower respiratory tract infections. 16 Broad Spectrum Penicillins Carbenicillin, Ticarcillin, and Piperacillin. Very poorly absorbed from the gut. They are susceptible to β- lactamases. Antibacterial spectrum is the same as the extended spectrum drugs plus pseudomonas. Ticarcillin is more potent against pseudomonads , available with clavulanic acid. P aeruginosa develops resistance during treatment, so a penicillin is frequently used in combination with an aminoglycoside or fluoroquinolone . Used in the treatment of urinary tract, lung, and bloodstream infections caused by ampicillin -resistant enteric gram-negative pathogens (e.g. E. coli). 17 Unwanted effects -hypersensitivity reactions (main side-effects) - Alter bacterial gut (GI disturbances, diarrhea). (More with extended spectrum). - All Penicillins, particularly Methicillin, have the potential to cause acute nephritis, thus Methicillin is no longer available. - All oral penicillins are best given on an empty stomach to avoid the absorption delay. Exception amoxicillin. 18 Cephalosporins β- lactam antibiotics isolated from a strain of Streptomyces. large number (70) available for clinical use, termed first- second- third- fourth generations. First-generation are active against Gram(+) bacteria, and successive generations have increased activity against Gram(-) bacteria with reduced activity against Gram-positive organisms. Bactericidal and work in the same way as the penicillins by interfering with the cell-wall. Only a few cephalosporins are administered orally , e.g. cephalexin, most are administered IM or IV. Their t½ are short & excreted in the urine. 19 First Generation Cephalexin Cefazolin effective orally IV, IM Effective against the same gram-positive organisms affected by penicillin G plus some Gram (-) bacteria (Proteus, E.coli and Klepsiella pneumonia). Excellent agents for skin and soft tissue infections caused by S. aureus and S. pyogenes. 20 Second generation Cefaclor Cefoxitin Cefuroxime Less effective against gram positive bacteria. Effective against H influenza, Entreobacter aerogenes and Nesseria sp. Some agents (cefoxitin) also active against the Bacteroides fragilis so can be used to treat mixed anaerobic infections such as peritonitis. Cefuroxime is used to treat community-acquired pneumonia because it is active against beta-lactamaseproducing H influenzae or K pneumoniae and penicillinresistant pneumococci. 21 Third Generation Ceftazidime , Ceftriaxone, Cefotaxime Cefoperazone Relatively weak against gram-positive but more potent against gram-negative bacteria including beta-lactamase producing Enterobacteriaceae. •some agents (ceftazidime and cefoperazone ) also is active against Pseudomonas aeruginosa. The third-generation, with or without aminoglycosides, are the drugs of choice for serious infections caused by Klebsiella, Enterobacter, Proteus, Serratia, and Haemophilus spp. 22 Ceftriaxone and cefotaxime -are the most active cephalosporins against penicillin-resistant strains of pneumococci and are recommended for empirical therapy of serious infections that may be caused by these strains. - Ceftriaxone is the therapy of choice for all forms of gonorrhea and for severe forms of Lyme disease (caused by Borrelia sp. transmitted via the bite of an infected tick. 23 Fourth generation Cefepime developed to fight against the resistant gramnegative bacteria. Cefepime has an extended spectrum of activity compared with the third generation. indicated for the empirical treatment of nosocomial infections particularly useful when gram-positive bacteria, Enterobacteriaceae, and Pseudomonas are potential etiologies. Cross blood-brain barrier and are effective in meningitis. 24 Adverse Effects Hypersensitivity, cross resistance with penicillin. GI system- Nausea, vomiting, diarrhea, anorexia, abdominal pain and flatulence are common effects. CNS – headache, dizziness, lethargy and paresthesias. Drug-Drug interactions Aminoglycosides, if given with cephalosporins may increase the risk of kidney toxicity Anti-coagulants- may experience increased bleeding tendencies ALCOHOL- many patients experience a disulfiram -like reactions. This may occur even up to 72 hours of cephalosporin discontinuance. 25 Carbapenems imipenem, and meropenem Broad spectrum β-Lactam antibiotics Highly resistant to most β-lactamases. Imipenem has a wide spectrum against many gramnegative rods, including Pseudomonas aeruginosa, gram-positive organisms, and anaerobes. Carbapenems are one of the antibiotics of last resort for many bacterial infections, such as E. coli and klebsiella pneumoniae. Recently, alarm has been raised over the spread of drug resistance to carbapenem antibiotics due to 26 production of carbapenemases Imipenem is inactivated by dehydropeptidases in renal tubules, so administered with cilastatin (inhibitor of renal dehydropeptidase) for UTI. A carbapenem is indicated for infections caused by organisms that are resistant to other drugs, e.g., P aeruginosa, and for treatment of mixed aerobic and anaerobic infections. A carbapenem is the beta-lactam antibiotic of choice for treatment of enterobacter infections because it is resistant to destruction by the lactamase . side-effects Nausea and vomiting been the most frequently At high doses neurotoxicity can occur. 27 Vancomycin A glycopeptide antibiotic, naturally occurring made by the soil bacterium first isolated in 1953. Bactericidal, acts by inhibiting cell wall synthesis. Active only against gram-positive bacteria, particularly staphylococci. primarily used for of serious infections caused by Gram-(+) bacteria resistant to other antibiotics. Not absorbed, given by slow IV (over 60 min). to avoid pain & thrombophlebitis and to avoid an infusion reaction known as the red man syndrome 28 first-line treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis infections caused by methicillin-resistant S. aureus. Oral vancomycin is is used for intestinal infection with Clostridium difficile, a common side effect of treatment with broad-spectrum antibiotics. Unwanted effects: fever, rashes and local phlebitis. Ototoxicity and nephrotoxicity can occur Hypersensitivity reactions are occasionally encountered. 29 Monobactams Aztreonam β- lactam antibiotic, activity is limited to aerobic gram-(-) rods (including pseudomonas). No activity against gram (+) bacteria or anaerobes. Resistant to most β -lactamases. •Penicillin-allergic patients tolerate aztreonam used to treat serious infections such as pneumonia, meningitis, and sepsis caused by gram-(-) bacteria. Side-effects: similar to other β -lactam antibiotics. 30 Protein Synthesis Inhibitors All protein synthesis inhibitors are bacteriostatic, except aminoglycosides Chloramphenicol is bacteriostatic but bactericidal against certain organisms. Because of overuse, resistance is common. Mechanism: Combine with the bacterial ribosomes & interferes with m-RNA ribosome combination which ultimately prevents protein synthesis. 31 TETRACYCLINES Doxycycline, Minocycline, Tetracycline Mechanism of action Bind to both mRNA & the ribosomal 30S subunit where they prevent the binding of aminoacyl-tRNA. By this mechanism, bacterial protein synthesis is inhibited •Bacteriostatic not bacteriocidal. Spectrum of activity is very wide and includes Gram-(+) and Gram-(-) bacteria, some spirochaetes & some protozoa (amoebae). 32 Resistance is common and is mainly due to a plasmidmediated efflux pump. Mutations in the tetracycline target site are also found. Administered orally but can be given parenterally. Absorption from the gut is irregular and better in the absence of food. Tetracyclines chelate di - and tri- valent metal ions, forming insoluble complexes, so absorption is decreased in the presence of milk, certain antacids & iron preparations. 33 Tetracyclines, con. Tetracyclines are the drugs of choice for: -Cholera -Chlamydia infection -Rocky mountain spotted fever caused by Rickettsia -Lyme disease caused by Borrella. -Mycoplasma pneumoniae which causes community acquired pneumonia -A tetracycline in combination with aminoglycoside is indicated for brucellosis -used in combination regimens to treat gastric and duodenal ulcer disease caused by Helicobacter p -Treatment of Acne 34 Tetracyclines, con. -Tetracycline is occasionally used in Dentistry to treat bacterial infections. -It concentrates in the gingival fluids around the teeth so it is often used to treat gingivitis and gum disease. -it is one of the first choices for the treatment of ANUG (Acute necrotizing ulcerative gingivitis ) Which appears with stress. 35 Tetracyclines, con. Doxycycline and Minocycline Prescribed for up to two weeks for different types of periodontal (gum) diseases, including juvenile periodontitis. Doxycycline even in very low doses can inhibit collagenase enzyme which breaks down collagen, and patients taking doxycycline can have fewer infections in skin and gum. Doxycycline , prescribed in a low dosage for up to nine months as an adjunctive therapy to dental scaling to shrink periodontal pockets and to arrest bone loss in adults with periodontal disease. The typical dose is 20 milligrams twice each day. 36 Tetracyclines, con. Side Effects: Most Common: GI disturbances (irritation) & modification of gut flora, causing Suprinfection & Candida infections (common) Deposited in growing bones & teeth, causing staining & sometimes dental hypoplasia & bone deformities. Phototoxicity: to sun or ultra-violet rays. Not given to children, pregnant women or nursing mothers. (may causes hepatotoxicity in pregnant women). 37 Chloramphenicol Broad-spectrum antibiotic. Active not only against bacteria, but also against other microorganisms, such as Rickettsia. Bactericidal or (more commonly) bacteriostatic, depending on the organism. Due to its toxicity, its use is restricted to life-threatening infections for which no alternatives exist. Mechanism of action Binds to the bacterial 50S ribosomal subunit and inhibits bacterial ribosomal and, to a lesser extent, mammalian mitochondrial protein synthesis. Pharmacokinetics IV or orally. widely distributed ,enters CSF. 38 Chloramphenicol, cont.. Chloramphenicol is indicated for: -Ampicillin-resistant H. influenzae infections. -Patients allergic to penicillin with pneumococcal, meningococcal or H. influenzae meningitis -treatment of brain abscess and other severe anaerobic infections (excluding endocarditis) due to Bacteroides fragilis Resistance -reduced permeability, mutation of the 50S ribosomal subunit, the presence of an R factor that codes for an acetyl coenzyme A transferase. This enzyme inactivates chloramphenicol. 39 Adverse Effects Chloramphenicol, cont.. Clinical use limited to life threatening infections because of serious side effects GI upsets, Overgrowth of Candida albicans Anaemias – hemolytic anemia Aplastic anemia, rare and usually fatal. Aplastic anemia is independent of dose and may occur after therapy has ceased. Gray baby syndrome – poor feeding, depressed breathing, cardiovascular collapse, cyanosis & Bone Marrow depression Interactions – blocks the metabolism of warfarin, phenytoin, tolbutamide & chlopropamide = increased effects of the drugs 40 MACROLIDES A group of antibiotics with a macrocyclic lactone structure to which one or more deoxy sugars are attached. Erythromycin was the first of these drugs, as an alternative to penicillin in individuals allergic to β lactam antibiotics. The newer members of this family clarithromycin, azithromycin & Telithromycin All are well absorbed orally. 41 macrolides cont. Mechanism of action macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting the translocation steps of protein synthesis. Bacteriostatic, they may be bactericidal at higher doses. Antibacterial spectrum Erythromycin: Effective against the same organisms as penicillin G , therefore, it may be used in patients who are allergic to the penicillins. Orally as enteric-coated tablets or esterified form. 42 macrolides cont. Clarithromycin: spectrum of antibacterial similar to erythromycin, but it is also effective against Haemophilus influenzae. Its activity against intracellular pathogens, such as Chlamydia, Legionella, Moraxella, and Ureaplasma species and Helicobacter pylori, is higher than that of erythromycin. 43 macrolides cont. Azithromycin: less active against streptococci & staphylococci than erythromycin. azithromycin is far more active against respiratory infections due to H. influenza and Moraxella catarrhalis. Azithromycin is now the preferred therapy for urethritis caused by Chlamydia. Also used for: Respiratory track infection. Urinary track infection & Otitis media 44 macrolides cont. Telithromycin Antibacterial spectrum similar to that of azithromycin. The structural modification neutralizes the most common resistance mechanisms (methylase -mediated and efflux-mediated) that make macrolide ineffective. 45 macrolides cont. Resistance most strains of staphylococci are resistant Several mechanisms have been identified: 1) Efflux pump limit the amount of intracellular drug. 2) Decreased affinity of the 50S ribosomal subunit due to methylation of an adenine in ribosomal RNA. 3) The presence of a plasmid-associated erythromycin esterase. Both clarithromycin and azithromycin show crossresistance with erythromycin, but telithromycin can be effective against macrolide-resistant organisms. 46 macrolides cont. Adverse effects 1. Epigastric distress: common Clarithromycin and azithromycin better tolerated but GI problems are their most common side effects. 2. Cholestatic jaundice: Erythromycin estolate is associated with reversible hepatotoxicity in pregnant women 3. Ototoxicity: Transient deafness with erythromycin, especially at high dosages. 4. Contraindications: Patients with hepatic dysfunction because these drugs accumulate in the liver. 47 Aminoglycosides Amikacin, Gentamicin, Tobramycin, & Neomycin. Gentamicin Were the mainstays for treatment of serious infections due to aerobic gram-negative bacilli. serious toxicities, replaced to some extent by safer antibiotics, such as the third- and fourth-generation cephalosporins, the fluoroquinolones, and the carbapenems. 48 aminoglycosides cont. Bactericidal protein synthesis inhibitor Bind to the ribosomal 30S Subunit, inhibit initiation of peptide synthesis and cause miss-reading of the genetic code. Effective against many aerobic Gram-negative and some Gram-positive bacteria, Their greatest use against Gram-negative enteric organisms & in sepsis. 49 aminoglycosides cont. Antibacterial spectrum Effective in combination for the empirical treatment of infections suspected of being due to aerobic gramnegative bacilli, including Pseudomonas aeruginosa. synergistic effect when combined with vancomycin, or a drug active against anaerobic bacteria. The aminoglycosides are effective only against aerobic organisms because strict anaerobes lack the oxygenrequiring drug transport system. Aminoglycosides may only be used as monotherapy for urinary tract infections (UTIs). 50 aminoglycosides cont. Resistance Resistance caused by 1) decreased uptake of drug 2) plasmid-associated synthesis of enzymes that inactivate aminoglycoside antibiotics. Amikacin is less affected by these enzymes Pharmacokinetics Not absorbed. Not metabolized, all aminoglycosides (except neomycin) must be given parenterally Because of severe nephrotoxicity associated with neomycin its current use is limited to topical application for skin infections or orally to prepare the bowel prior to surgery. 51 aminoglycosides cont. The bactericidal effect of aminoglycosides is concentration and time dependent, the greater the concentration of drug, the greater the rate at which the organisms die. Also have a post antibiotic effect. One dose/day adequate. Distribution: Concentrations in CSF are inadequate. Except for neomycin, the aminoglycosides may be administered intrathecally or intraventricularly. All aminoglycosides cross the placental barrier and may accumulate in fetal plasma and amniotic fluid. Fate: Not metabolized. All are rapidly excreted into the urine. Accumulation occurs in patients with renal failure 52 aminoglycosides cont. Clinical uses 1) Gram – ve bacillary infection – septicemia, pelvic & abdominal sepsis 2) Bacterial endocarditis – enterococcal, streptococcal or staphylococcal. 3) Pneumonias, Tuberculosis 4) Brucellosis 5) Neomycin is used to sterilize the bowel of patients who receive immunosuppressive therapy, before surgery. 53 aminoglycosides cont. Gentamycin is the First choice due to low cost, reliable activity and long experience of use. Used in infected burns, otitis externals, acute pyelonephritis Tobramycin is the most active against Pseudomonas infections Amikacin is the Broadest antibacterial spectrum. Preferred in serious nosocomial G –ve bacillary infection in hospitals where Tobramycin & Gentamycin have developed resistance 54 aminoglycosides cont. Adverse effects 1. Ototoxicity:. Deafness may be irreversible and affect fetuses in uterus. Vertigo and loss of balance 2. Nephrotoxicity: mild, reversible renal impairment to severe, acute tubular necrosis, which can be irreversible 3. Neuromuscular paralysis: after large IP or intrapleural doses. Patients with myasthenia gravis are particularly at risk. 4. Allergic reactions: Contact dermatitis to topically applied neomycin 55 Clindamycin Antibiotic of of the lincosamide class Binds to the 50S ribosomal subunit and inhibit the correct attachment of the amino acid end of aminoacyl-tRNA. -treat infections with anaerobic bacteria, but can also treat protozoal disease, such as malaria. -tropical treatment of acne -useful against some methicillin -resistant S. aureus. main clinical use in infections caused by bacteroides and staphylococcal infections of bones and joints. . 56 Clindamycin is a highly effective when used to fight dental infections. It is 90% absorbed & penetrates deeply into the soft tissues of the body, as well as bone, where dental infections reside. used in combination with an aminoglycoside or cephalosporin to treat penetrating wounds of the abdomen and the gut; -Treat infections in the female genital tract, e.g., septic abortion and aspiration pneumonia. Side-effects : GI upsets but its most severe common adverse effect is Clostridium difficile associated diarrhea, the most frequent cause of pseudomembranous colitis. 57 FLUOROQUINOLONES Naladixic acid is the predecessor to all fluoroquinolones Mechanism of action quinolone binds to both the DNA gyrase enzyme & the DNA. This inhibits the resealing step, and cause cell death. Cross-resistance with other antimicrobial drugs is rare. Broad spectrum antibiotic active against both Gramnegative and Gram-positive bacteria. more active against Gram-negative species. First oral antibiotics effective against gram-negative bacteria. 58 Ciprofloxacin is the most commonly used fluoroquinolone. Ciprofloxacin most active agent against gram-negatives, Pseudomonas aeruginosa in particular Levofloxacin, and moxifloxacin improved activity against gram-positive organisms, particularly S. pneumoniae and some staphylococci. used increasingly for treatment of upper and lower respiratory tract infections. 59 Their main uses are: - complicated urinary tract infections - respiratory infections - Infections of soft tissues, bones, and joints and in intra-abdominal - bacterial prostatitis and cervicitis -Also used in bacterial diarrhoea caused by shigella, salmonella, E. coli. Side-effects: mild. GI disorders (nausea, vomiting, and diarrhea) and skin rashes. 60 Sulfonamides Mechanism of action sulfonamides are synthetic analogs of PABA.They inhibit the synthesis of dihydrofolic acid and the formation of its essential cofactor forms. The sulfa drugs are bacteriostatic. Antibacterial spectrum active against Enterobacteria in the urinary tract. Resistance may be due to 1)an altered dihydropteroate synthetase, 2) decreased cellular permeability to sulfa drugs, or enhanced production of PABA. 61 Sulphonamides are available as: (1) Oral Absorbable Agents: Sulfisoxazole and sulfamethoxazole. almost exclusively to treat urinary tract infections. (2) Oral Nonabsorbable Agents Sulfasalazine is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease (3) Topical Agents Silver sulfadiazine is used for prevention of infection of burn wounds. 62 Side effects: mild to moderate side-effects including, nausea, vomiting, headaches, and depression. More serious side-effects include hepatitis, hypersensitivity reactions, bone marrow depression, and aplastic anemia. Sulfonamides may provoke hemolytic reactions in patients with glucose-6phosphate dehydrogenase deficiency. 63 TRIMETHOPRIM Antibacterial spectrum similar to sulfonamides. Trimethoprim compounded with sulfamethoxazole, producing the combination called cotrimoxazole. A. Mechanism of action inhibitor dihydrofolate reductase leading to a decreased availability of the tetrahydrofolate coenzymes required for purine, pyrimidine, synthesis. Antibacterial spectrum Similar to that of sulfamethoxazole. However, it is 20- to 50-fold more potent than the sulfonamide. Trimethoprim may be used alone in the treatment of acute UTIs and in the treatment of bacterial prostatitis and vaginitis. 64 COTRIMOXAZOLE Combination of trimethoprim with sulfamethoxazole Greater activity than either drug used alone Mechanism of action The synergistic activity results from its inhibition of two sequential steps in the synthesis of tetrahydrofolic acid: sulfamethoxazole inhibits folic acid production, and trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate. Effective in UTIs, prostatitis and respiratory tract infections as well as in ampicillin- or chloramphenicolresistant systemic salmonella infections. 65