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Nursing 3703 Pharmacology Antimicrobials By Linda Self Microorganisms and Infections Microbes attach to host receptors Attracted to a specific body tissue, invade and multiply Most survive in more than one type of environment Symptoms are result of immune response Age-Related ConsiderationsChildren Penicillins and Cephalosporins generally safe Fewer clinical trials on children Erythromycin, Zithromax (azithromycin) and Biaxin (clarithromycin) considered safe Antimicrobials and Children Aminoglycosides can cause ototoxicity and nephrotoxicity. Tetracyclines are contraindicated in children younger than 8 years old, effects on teeth Cleocin (clindamycin) admin. requires liver and kidney monitoring in neonates and infants Antimicrobials and Children Fluoroquinolones contraindicated in children under 18 yo. May have effects on weight bearing joints. Bactrim (trimethoprimsulfamethoxazole) no longer 1st line due to resistance Antimicrobials and Older Adults Penicillins are generally safe, IV admin. can cause hyperkalemia Cephalosporins are considered sage but can affect or worsen renal failure Macrolides are generally safe Aminoglycosides are contraindicated in severe renal impairment Antimicrobials and Older Adults Aminoglycosides can also cause ototoxicity Cleocin (clindamycin)-diarrhea, colitis Bactrim (trimethoprimsulfamethoxazole) may be associated with impaired liver or kidney function Antimicrobials and Older Adults Tetracyclines (except doxycycline) and Macrodantin (nitrofurantoin) are contraindicated in impaired renal function In General With most oral antibiotics, liberal fluid intake is recommended Always be aware of pregnancy category before administering medication Bacteria Aerobic Anaerobic Gram’s Stain-microscopic appearance and color Pathogenic Normal flora Lab ID of Pathogens Culture and sensitivity Serology-measures antibody levels Polymerase Chain Reaction (PCR) detects the specific DNA for a specific organism Common Human Pathogens Viruses Gram+ enterococci, streptococci and staphylococci Gram- organisms: E.coli, Bacteroides, Klebsiella, Proteus, Pseudomonas Opportunistic Community-acquired vs. nosocomial Antibiotic-Resistant Microorganisms Occurs when: Clinical condition of host is impaired Normal flora have been suppressed w/interrupted or inadequate tx Type of bacteria Widespread use of broad spectrum abx Environmental setting of host Mechanisms of Resistance By: Generating enzymes that inactivate the antibiotic (beta lactamase) Changing structure of target site (beta lactams and aminoglycosides) Preventing cellular accumulation of abx by altering outer membrane proteins or using efflux pumps Mechanisms of Resistance cont. Changing the metabolic pathway that is being blocked Overproducing the target enzyme to overpower the effects of antibiotics Gram negatives possess an outer membrane and cytoplasmic membrane preventing passage of abx through porins Mechanisms of Resistance cont. Mycoplasma lacks a cell wall makingit impervious to penicillins Sulfonamides have no impact on bacteria that obtain their folate from environment Characteristics of Anti-Infectives Includes antibacterials, antivirals and antifungals Antibacterials (antibiotics) refer to drugs which treat bacterial infections Narrow spectrum Broad spectrum Bactericidal (kills) vs. Bacteriostatic (inhibits) Host Defense Mechanisms Breaks in skin and mucous membranes Impaired blood supply Neutropenia Malnutrition Poor personal hygiene Suppression of normal flora Diabetes, advanced age or immunosuppression Mechanisms of Action Inhibition of bacterial cell wall synthesis or activation of enzymes that disrupt cell walls (PCNs, Cephalosporins, Vancomycin_ Inhibition of protein synthesis (EES, tetracyclines, clindamycin, aminoglycosides) Mechanisms of Action cont. Disruption of microbial cell membranes (anti-fungals) Inhibition of organism reproduction by interfering w/nucleic acid synthesis (fluoroquinolones, HIV antiretrovirals) Inhibition of cell metabolism and growth (sulfonamides) Prophylactic Therapy or Empiric Therapy STD exposure Recurrent UTIs TB Perioperative infections in high risk patients or high risk surgeries Bacterial endocarditis—w/cardiac valvular disease undergoing dental, surgical or other invasive procedures Drug Selection Best if based on culture and sensitivity—”match the drug to the bug” MIC—minimum inhibitory concentration—lowest concentration of a drug that prevents visible growth of microorganisms Drug Selection cont. Knowledge of organisms likely to infect particular body tissues Other Selection Considerations Drug’s ability to penetrate infected tissues (prostate, sinuses) Drug’s toxicity and the risk-to-benefit ratio Drug costs Antibiotic Combination Therapy Used when infection is caused by multiple microorganisms Nosocomial infections Serious infections in which a combination is synergistic (aminoglycoside and antipseudomonal PCN) Antibiotic Combination Therapy cont. Likely emergence of drug resistant organisms In those who are immunosuppressed Beta Lactams Contain a beta-lactam ring that is part of their chemical structure An intact beta-lactam ring is essential for antibacterial activity Include: Penicillins, Cephalosporins, Carbapenems and Monobactams Beta Lactam Mechanism of Action Inhibit synthesis of bacterial cell walls by binding to proteins in bacterial cell membranes Binding produces a defective cell wall that allows intracellular contents to leak out Most effective when bacterial cells are dividing Penicillins Derived from a fungus Prototype is Penicillin G Widely distributed except in CSF (except if inflammation is present) and in intraocular fluid Most serious complication is hypersensitivity. Can cause seizures and nephropathy. Indications for Penicillins More effective in treating gram+ infections Used to treat infections of the skin, GU, GI, respiratory tract and soft tissues Selection depends on the organism and severity of the infection—anti-staph vs. anti-pseudomonal Combinations for beta lactamase inhibition (Augmentin) Examples of Penicillins Penicillins G and V (parenteral); dicloxacillin (antistaph); Ampicillins—Principen, Amoxil Antipseudomonals—Geocillin (carbenicillin), Ticar (ticaracillin), Pipracil (piperacillin) Combinations for beta lactamase— Unasyn (ampicillin/sulbactam), Zosyn (piperacillin/taxobactam) Examples Antistaphylococcal—dicloxacillin, nafcillin Anti-pseudomonals—carbenicillin, ticaracillin Beta lactamase inhibition combinations: Unasyn (ampicillin/sulbactam), Augmentin (amoxicillin/clavulate), Timentin (ticaricillin/clavulanate) Cephalosporins Also derived from a fungus Broad spectrum with activity against both gram positive and gram negative bacteria Less active against gram positives than penicillins Do not penetrate CSF well w/exception of Ceftin (cefuroxime) and 3rd generation agents Cephalosporins Progressively more effective against gram negative pathogens as progress generationally indications-surgical prophy, tx infections of the respiratory tract, skin, bone and joints, urinary tract, brain and spinal cord and in septicemia Cephalosporins Contraindicated in anaphylaxis to a penicillin May develop a delayed reaction Examples Oral—Keflex (cephalexin); Ceclor (cefaclor), Lorabid (lorcarbef); Omnicef (cefdinir) Parenteral—Ancef (kefzol); Mefoxin (cefoxitin); Claforan (cefotaxime), Fortaz (ceftazidime), Rocephin (ceftriaxone); Maxipime (cefepime) Carbapenems Broad spectrum, bactericidal, betalactam anti-microbials. Inhibit synthesis of cell walls. All are parenteral Indicated for organisms resistant to other drugs Examples: Merrem (meropenem) and Primaxin (imipenem-cilastatin) Monobactams Azactam (aztreonam) is active against gram-negative bacteria and to many resistant strains Similar to aminoglycosides but no kidney damage nor hearing loss Stable in presence of beta lactamase Preserves normal gram positive and anaerobic flora Indications for Monobactams Infections of the: Urinary tract Lower respiratory tract Skin and skin structures Intra-abdominal and gynecologic infections Septicemia FYI Penicillins may be given with Probenecid or aminoglycosides for serious infections PCN can cause nephropathies Ticaracillin has been linked to hypernatremia PCN G can cause hyperkalemia Caution w/Augmentin in hepatic impairment FYI Need to adjust dosages of all beta lactams in the presence of renal impairment whether PCN, cephalosporins, carbapenems and monobactams Aminoglycosides Bactericidal agents to treat gram negative organisms such as: Proteus, Klebsiella, Enterobacter, Serratia, Escherichia coli, and Pseudomonas Poorly absorbed fro the GI tract so cause local effects Accumulate in kidneys and ears Poorly distributed to CNS, respiratory tract and intraocular fluids Oral forms excreted in feces, injectables by kidneys Aminoglycosides cont. Mechanism of action by penetrating cell walls of susceptible bacteria and bind to 30S ribosomes. Bottom line— prevent protein synthesis and replication. Indicated for serious gram negative organisms Most often affect the respiratory, GU, skin, wound, bowel and bloodstream Aminoglycosides cont. Penicillin facilitates entry of aminoglycosdie through the bacterial cell wall Streptomycin is useful in tuberculosis Synergism when used with vancomycin, ampicillin or penicillin G in tx of enterococcal infections Used to suppress intestinal flora in those with hepatic failure Aminoglycosides cont. Contraindicated in infections for which less toxic drugs are effective These drugs are nephrotoxic and ototoxic Must use cautiously in Myasthenia Gravis or neuromuscular disorders because muscle weakness may be increased Aminoglycosides cont. Choice depends on local susceptibility patterns Gentamycin generally chosen first, then Tobramycin or Amikacin Dosing must be carefully regulated because therapeutic doses are close to toxic doses Aminoglycosides—Management Considerations Initial loading dose based on ideal weight Are not distributed in body fat Maintenance doses are based on serum drug concentrations. Peak levels should be assessed 30-60 minutes after administration. Aminoglycoside—Management Considerations cont. Measurement of peak and trough levels helps to maintain therapeutic serum levels w/o excessive toxicity With impaired renal function, dosage of aminoglycosides must be reduced. Dosages or intervals may be reduced. In UTIs, may use lower dosage as excreted by kidneys Daily dosing Fluoroquinolones Synthetic bactericidal drugs with activity against gram positive and gram negative organisms Most are given orally Excreted via kidneys Mechanism of action is by interfering with DNA gyrase, an enzyme necessary for synthesis of bacterial DNA Fluoroquinolones May be used to treat respiratory, GU, GI, bones, joints, skin and soft tissues. Useful in multi-drug resistant TB, Mycobacterium avium complex patients, for fever in neutropenic patients and in tx of gonorrhea. Fluoroquinolones cont. Contraindicated in hypersensitivity reactions In children under 18 years of age In pregnant or lactating women Examples of quinolones: Cipro (ciprofloxacin), Levaquin (levofloxacin), Floxin (ofloxacin) Pregnancy category C Fluoroquinolones cont. Monitor renal and liver function Ensure adequate fluid intake to prevent crystalluria Assess current medications for drugs that interact with Avoid exposure to sunlight Macrolides Include: Zithromax (azithromycin), Biaxin (clarithromycin), EES (erythromycin) and Dynabac (dirithromycin) Effective against gram positive cocci, Neisseria, Treponema, Mycoplasma,Bacteroides, Clostridia and Corynebacterium Macrolides Erythromycin is the prototype Food can have an effect on absorption New relative, Ketek (telithromycin) called ketolides. Will offer better activity against multi-drug resistant strains of Streptococcus. Macrolides Mechanism of action is by entering microbial cells and attaching to 50S ribosomes, thereby inhibiting microbial protein synthesis EES is PCN alternative Indications for Macrolides Respiratory tract infections Skin and soft tissue infections caused by Staph and Strep For Legionnaire’s and GU infections caused by Chlamydia Clarithromycin is indicated for tx of MAC and for H. pylori Macrolide Management Considerations EES interferes with the elimination of drugs metabolized by the cytochrome P450 enzymes Interacting drugs include: Coumadin, Theophylline, Prednisone, Norpace, Lanoxin, Tegretol, Alfenta and Parlodel (dopamine agonist) Macrolides Contraindicated in liver disease Contraindicated in hypersensitivity Miscellaneous Antibacterials Chloramphenicol—broad spectrum bacteriostatic used for gram negative and positive bacterial infections More toxic than others that can do equally well for gram positives Indicated in meningococcal, pneumococcal, rickettsial infections and in Haemophilus and Klebsiella Miscellaneous Cleocin (clindamycin)—similar in actio to macrolides; is effective against gram positive cocci and pneumococci Effective in treating mixed infections Great for acne and bacterial vaginosis Can cause pseudomembranous colitis Miscellaneous Zyvox (linezolid) is a member of the oxalodinone class Active against aerobic gram positive bacteria Indicated for septicemia Can cause myelosuppression and psedomembranous colitis Miscellaneous Flagyl (metronidazole) Effective against anaerobic bacteria, gram positive bacilli such as clostridium and protozoa such as Giardia, amebiasis, trichomoniasis Useful topically for rosacea Used for bacterial vaginosis Disulfiram-like reaction if taken w/alcohol Miscellaneous--Vancomycin Active against gram positives only Frequently used to treat MRSA Can cause hypotension, flushing and skin rash if given too quickly Resistance is mounting Can cause “red man sydrome” if given too quickly Caution in patients w/myasthenia gravis Drug interactions Amphotericin B, vancomycin, cephalosporins, loop diuretics, neuromuscular blocking agents can increase the effects of aminoglycosides Tagamet (cimetidine) and Probenecid increase the effects of the fluoroquinolones Drug Interactions cont. Chloramphenicol and Streptomycin increase the effects of EES Tagamet increases the action of Flagyl Others, see text Syndercid (quinupristindalfopristin) Effective in vancomycin resistant strains MRSA Strong inhibitor of cytochrome P450 Belong to a class called streptogramins Caustic to veins Tetracyclines Broad spectrum bacteriostatic Microbial resistance emerging Newer options less toxic Still very effective against rickettsiae (e.g. Rocky Mountain Spotted Fever) Effective against Chlamydia, Mycoplasma, protozoa (e.g. Malaria, Giardia, Leishmaniasis) Tetracyclines Most are excreted in urine Examples include: Minocin (minocycline), Vibramycin (doxycycline), Achromycin (tetracycline) Tetracyclines Work by passive diffusion and an active transport system Bind to 30S ribosomes and inhibit micorbial protein synthesis Drugs of choice in Brucellosis, Chancroid, Cholera, Granuloma Inguinale, Trachoma, H. pylori Indications for use Treatment of uncomplicated urethral, endocervical or rectal infections caused by chlamydia Adjunt in the treatment of PID and STDs Long term treatment of acne (interfere with production of free fatty acids and Corynebacterium in sebum) Indications for use on tetracyclines cont. May be used as substitute for penicillin Doxycycline may be used for Traveller’s diarrhea Declomycin (demeclocycline) may be used to inhibit ADH in management of chronic SIADH Tetracyclines cont. Contraindicated in renal failure except for doxy and minocycline Not indicated in children less than 8 years of age because can cause permanent discoloration of teeth and can depress bone growth Can cause photosensitivity Avoid taking within 2 hours of dairy products, w/iron or w/antacids Sulfonamides Bacteriostatic against both gram positive and gram negative bacteria Resistance is mounting Combination of Bactrim (trimethoprim-sulfamethoxazole) is useful in the treatment of urinary tract infections and in Pneumocystis carinii Sulfonamide preparaions Azulfidine (sulfasalazine) is used in tx of ulcerative colitis and in RA May cause crystalluria. Liberal fluids needed. Sulfonamides cont. Sulfamylon used in burns—especially w/Pseudomonas—can cause metabolic acidosis, is painful w/application Silver sulfadiazine—useful in burns Miscellaneous Drugs for UTIs Macrodantin (nitrofurantoin) Pyridium (phenazopyridine)-no antibacterial activity, acts as urinary antiseptic Questions? Sulfonamides Contraindicated in renal failure Can cause bone marrow depression, especially in elderly With Bactrim, can cause folic acid deficiency Can cause cholestatic jaundice in rare cases