BETA LACTAM ANTIBIOTICS AND OTHER CELL WALL SYNTHESIS INHIBITORS Ma. Shiela Cano-Guiking, M.D. PENICILLINS I. CLASSIFICATION A. Penicillinase Resistant ( Antistaphylococcal Penicillins) 1. Methicillin ( Staphcillin) 2. Nafcillin (Unipen, Nafcil, Nallpen) 3. Isoxazolyl penicillins a. Oxacillin b. Cloxacillin c. Dicloxacillin d. Flucloxacillin B. Penicillinase-Susceptible 1. Narrow-Spectrum a. Benzylpenicillin – Penicillin G b. Phenoxymethyl penicillin – Penicillin V 2. Extended Spectrum A. Aminopenicillins a.1 Ampicillin a.2 Esters a.2.1. Bacampicillin a.2.2. Pivampicillin a.2.3. Talampicillin a.3. Amoxicillin B. Carboxypenicillins a.1 Carbenicillin a.1.1. Indanyl carbenicillin e.g Geopen a.1.2. Disodium carbenicillin e.g. Pyopen a.2. Ticarcillin a.3. Temocillin C. Ureido-penicillins c.1. Mezlocillin c.2. Azlocillin c.3. Piperacillin c.4. Apalcillin II. GENERAL PROPERTIES A. Chemical Properties Penicillins are derivatives of benzylpenicillin, from which the methyl benzene radical is split off by amidase producing 6-aminopenicillanic acid, the parent compound of all semisynthetic penicillins The compound consists of 2 basic structures: 1 Thiazolidine Ring (A) 2.Beta-Lactam Ring (B) - Site of action of Beta-lactamase - Site of action of Amidase - Site of attachment of side chain ®, which determines many of the antibacterial and pharmacologic characteristics of a derivative ( spectrum and penicillin-resistance) Mechanisms of Action: Specific: inhibit the last step in the peptidoglycan synthesis of the cell wall Underlying: 1. inhibition of transpeptidase enzymes 2. activation of penicillin binding proteins (PBPs) 3. activation of autolysins (murein hydrolases) C. Mechanisms of Resistance • 1. inactivation of antibiotic by Beta lactamases 2. modification of PBPs 3. impaired penetration of drug to target PBPs 4. presence of an efflux pump Kinetics: - absorption vary with the preparation depending on their acid stability and protein binding - absorption of most oral penicillins (except amoxicillin) impaired by food and drugs should be given 1-2 hours before or after meal; parenteral – complete and rapid cannot penetrate the blood-brain barrier; but 50% of the plasma concentration can pass through in the presence of inflammation: - Probenecid and certain organic acids can inhibit transfer from cerebrospinal fluid (CSF) to blood stream; may lead to increase CSF level. - Metabolized by the liver to penicillanic/penicillenic acid; penicillamine, penicilloic acid and other penicilloyl derivatives (allergenic metabolites) - Excreted primarily by the kidneys (90% tubular secretion, 10% glomerular filtration) small amount through bile and feces, sputum and milk; renal excretion inhibited by probenecid E. Adverse Effects: 1. Hypersensitivity reactions most common adverse effects - cause the highest incidence of antibiotic allergy a. major antigenic determinant- penicilloyl metabolite skin testing( penicilloyl polylysine (PPL) ) b. Signs and symptoms: - varied skin rashes and purpuric reactions - angioedema and anyaphylactic reactions - fever - eosinophilia - interstitial nephritis 2.Gastrointestinal disturbances after oral administration 3.Convulsions following rapid IV administration 4. Accidental injection into the sciatic nerve – severe pain and nerve dysfunction persisting for weeks 5. Chronic use may cause: hepatitis overgrowth of minor/atypical organisms following use of broad spectrum preparations 6. Specific toxicities: a. Procaine Penicillin G after accidental IV injection: pulmonary embolism acute psychotic reactions b. Oxacillin and Nafcillin hepatitis granulocytopenia, bone marrow depression c. Disodium Carbenicillin and high dose Penicillin G Na -hypernatermia d. Penicillin G Potassium hyperkalemia with high doses e. Penicillin G Sodium Jarisch_herxheimer reaction with high doses in secondary syphilis f. Carbenicillin and Ticarcillin bleeding diathesis g. Methicillin interstitial nephritis h. Ampicillin associated with pseudomembranous colitis III. INDIVIDUAL AGENTS A. Penicillin G 1. Antimicrobial Spectrum - Streptococci, meningococci, enterococci, pen. susceptible pneumococci, non-B lactamase producing staph, Treponema, spirochetes, B. anthracis, Clostridium, Actinomyces, G(+) rods and non B lactamase producing G (-)anaerobic organisms 2.Kinetics - 1/3 of oral dose absorbed from intestinal tract rapidly; food impair absorption - maximal concentration: 30-60 min. - intravenous a. Aqueous Penicillin G - peak in 15-30 min -T ½ - 0.5-2 hrs. - intramuscular B. Procaine Penicillin G peak in 1-3 hrs. T1/2 – 12 hrs. C. Benzathine Penicillin G mean duration of antimicrobial activity - 26 days - 60% albumin bound - widely distributed to the tissues and body fluids - does not readily enter the cerebrospinal fluid when meninges are not inflamed - probenecid and uremia inhibits active transport secretion into the blood stream Preparations: “ International Units “ – measure of strength Oral Preparations: Penicillin G Sodium Penicillin G Potassium Parenteral Preparations 1.short acting a. aqueous Penicillin G Potassium – 1.7 meq K/1M “u” b. aqueous Penicillin G Sodium – 2.4. meq Na/1M “u” 2. long acting a. Procaine Penicillin G – 300,000 – 600,000 “u” 120 mg procaine/vial b. Benzathine Penicillin G – 600,000 “u” 1.2 M “u”/vial 4. Doses and Therapeutic Uses a. Aqueous Penicillin G Child: mild infections – 50,000 “u” – 100,000 “u”/kg/day in equally divided Doses every 4-6 hrs. for 7 days Severe infections – 200,000 “u” – 600,000 “u”/kg/day in equally divided Doses every 2-6 hrs. for 14 days. a. Procaine Penicillin G – 300,000 – 600,000 “u” IM OD or BID for 7 days for Adults b. Benzathine Penicillin G – 1.2 million – 2.4 “u” IM monthly Syphilis – less than 1 year duration – 2.4 M “u” IM + Probenicid 1 gm/day for 10 days or 2.4 M “u” Benzathine Penicillin G IM single dose late latent, complicated – 20 M “u” aqueous Penicillin G/day for 10 days congenital syphilis – 50,000 “u”/kg/day aqueous Penicillin G for 10 days Staphylococcal infections Gram (+) anaerobes Meningococcal infections Gonococcal infections Carrier state diphtheria Other unusual infections – actinomycosis, Anthrax, rat bite fever, listeria, pasteurella, lyme disease, erysipeloid Prophylaxis – recurrences of streptococcal, rheumatic fever, gonorrhea, syphilis, bacterial endocarditis D . Penicillin V Oral form indicated only in minor infections Relative poor bioavailability; need for dosing 4x a day Gram (+) aerobic activities similar to Penicillin G 5-10x less active against gram(-) microbes, esp. Neisseria and certain anaerobes better absorbed from the gastrointestinal tract because of better acidic stability D. Ampicillin 1. Microbial Spectrum Somewhat less active than Penicillin G against gram (+) cocci Enterococcal grp. D and viridans grp. Of streptococci - Listeria monocytogenes - H. influenza Effective for Shigellosis Should not be used for uncomplicated salmonella gastroenteritis – may prolong the carrier state 2. Kinetics: Gastric acid stable and well absorbed from the gastrointestinal tract Orally absorbed drug peaks in 2 hrs. Intramuscular administered drug peaks in 1 hour Mainly excreted by the kidneys; also thru the bile and feces Undergoes enterohepatic circulation Other kinetic properties similar to Penicillin G Sodium 3. Adverse Effects: “Ampicillin skin rash” – occurs in 7-8% others similar to Pen G 4. Preparations a. Oral Capsules – 250-500 mg Suspension – 125 mg, 250 mg/5 ml Drops – 100 mg/ml b. parenteral 250 mg; 500 mg/ml vial 5. Doses a. mild infections Newborn – 25-50 mg every 12 hrs. Child – 50-100 mg/kg/d in 4-6 divided doses Adult – 1-4 gm/day b. severe infections Child – 200-600 mg/kg/day Adult – 6-12 gm/day E. Esters of Ampicillin No inherent antimicrobial activity as esters, but pharmacologically active following hydrolysis to Ampicillin 50% higher blood concentration than Ampicillin and Amoxicillin F. Amoxicillin Closely related to Ampicillin in chemical and pharmacologic properties More rapidly and completely absorbed from gastrointestinal tract Attains higher serum levels than ampicillin G. CARBOXYPENICILLINS AND UREIDOPENICILLINS 1. Antimicrobial Spectrum Gram (-) aerobes Pseudomonas aeroginosa Bacteroides fragilis; but in higher amount/dose Carboxypenicillins – certain indole (-) Proteus Ureidopenicillins – Klebsiella Azlocillin – 10x more active than carbenicillin against Pseudomonas 2.Preparations a. Carbenicillin Disodium salt – contains approximately 5 meq sodium/gm for parenteral administration Indanyl esters – 500 mg tablets b.Ureidopenicillins Parenteral preparations H. Penicillinase-Resistant 1. Methicillin -15-80x more active against penicillinase producing microbes than Penicillin G; only parenterally available; currently many resistant strains of Staph. Aureus have emerged, no longer used because of nephrotoxicity 2. Nafcillin – slightly more active than Cloxacillin against penicillinase producing Staph. Aureus, available in oral and parenteral preparations: GIT absorption is erratic 3. Isoxazolyl Penicillins Stable in gastric acid and adequately absorbed after oral administration Dicloxacillin is most active against penicillinase producing Staph. Aureus CEPHALOSPORINS I. CLASSIFICATION A. First Generation 1. Cephaloridine-Loridine, Ceporan 2. Cephalothin-Keflin 3. Cephalexin-Keflex, Ceporex 4. Cefazolin-Cefacidal 5. Cephradine-Velosef 6. Cepharpirin-Cefadyl 7. Cephadroxil-Doricef, Cefamox – B. Second Generation 1. Cefaclor-Ceclor 2. Cefoxitin – Mefoxin 3. Cefuroxime – Zinacef, Zinnat 4. Cefonicid – Monocid 5. Cefotetan - Cefotan 6. Cefamdandole – Mandol 7. Cefprozil – Cefzil 8. Loracarbef – Lorabid 9. Cefmetazole – Zefazone 10. Ceforanide C. Third Generation 1. Cefotaxime – Claforan 2. Cefoperazone – Cefobid 3. Moxolactam – Moxam 4. Ceftizoxime – Cefizox 5. Ceftriaxone – Rocephin 6. Ceftazidime – Fortum 7. Cefotiam – Ceradolan 8. Cefixime – Suprax 9. Cefetamet – Globocef 10. Cefpodoxime – Vantin 11. Ceftibuten – Cedax 12. Cefdinir –Omnicef 13. Cefditoren D. Fourth Generation 1. Cefepime – Maxipime 2. Cefpirome – Cefrom II. BASIS FOR CLASSIFICATION A. Antimicrobial Spectrum B. Pharmacokinetic Properties III. GENERAL PROPERTIES A. Chemistry 7-amino cephalosporanic acid – parent compound contains an R2 that makes the compound stable in dilute acid and highly penicillinase resistant * MW – 400-450 *Soluble to water and relatively stable to ph and temperature changes C7 modifications alter antibacterial activity C3 substitutes change metabolism and kinetic properties B. MECHANISM OF ACTION AND RESISTANCE Similar to penicillins C. Antimicrobial Spectrum Generally broader spectrum than Penicillins Generally more effective than Penicillins against B- lactamase-producing microbes (except enterococci, Methicillin-resistant Staph. aureus and Staph. epidermis) D. SPECIFIC GROUPS/INDIVIDUAL AGENTS 1. FIRST GENERATION Good activity against gram (+) and modest against gram (-) microbes Penetration of the cerebrospinal fluid (CSF) is inadequate UTI, minor staph lesions, minor polymicrobial infections – cellulitis, soft tissue abscess Not used in serious systemic infections 2. SECOND GENERATION Better activity against anaerobes and gram (-) aerobes Only Cefuroxime can produce sufficient CSF level Sinusitis, otitis, LRTI, mixed anaerobic infections such as peritonitis/diverticulitis 3. THIRD GENERATION Generally less active than the first generation against gram (+) cocci but most active against gram (-) including B-lactamase- producing strains Cefoperazone, Ceftazidime – (more active) against Pseudomonas Active against anaerobes – Cefoperazone, Cefotaxime Ceftizoxime, Moxolactam – B. fragilis Cefoperazone & Ceftriaxone -excreted primarily in the bile; Probenecid does not affect renal excretion Cross BBB except Cefoperazone, Cefixime, Ceftibuten and Cefpodoxime proxetil Ceftriaxone, 125 mg inj., Cefixime, single 400 mg oral dose -N. gonorrhea Cefoperazone –(T1/2 – 2 hrs. ) 25-100 mg/kg/d injected q 8-12 hrs Cefixime 200 mg orally twice a day or 400 mg OD Cefpodoxime proxetil & Ceftibuten – 200 mg 2x/day Meningitis caused by pneumococci, meningococci, H. influenza & susceptible enteric gram (-) rods but not by L. monocytogenes; should be used in combination with aminoglycoside for the treatment of meningitis caused by P. aeruginosa. 4. FOURTH GENERATION More resistant to hydrolysis by chromosomal beta lactamases (eg. Those produced by enterobacter) Good activity against P. aeruginosa, enterobacteriaceae, staph. aureus, S. pneumoniae Highly active against Haemophilus & Neisseria Penetrates well into CSF Cleared by kidneys T1/2 – 2 hrs Good activity against most penicillin resistant strains of streptococci Useful in the treatment of enterobacter infections E. ADVERSE EFFECTS 1. Allergy 2. Toxicity: 3. Renal toxicity – interstitial nephritis and even tubular necrosis Cephalosporin that contains a methyl thiotetrazole group ( Cefamandole, Cefmetazole, Cefotetan, Cefoperazone) – cause disulfiram like reactions, hypoprothrombinemia and bleeding disordersAntidote: Vit K, 10 mg 2x/week Moxolactam – interferes with platelet function, severe bleeding 4. Superinfection MONOBACTAMS Monocyclic beta lactam ring Resistant to B-lactamase Active against gram (-) rods including Pseudomonas and Serratia Aztreonam – resembles aminoglycosides in spectrum of activity Given 1-2 g IV q 8 hrs.; T1/2 – 1-2 hrs BETA LACTAMASE INHIBITORS ( CLAVULANIC ACID, SULBACTAM & TAZOBACTAM) Resemble B- lactam molecules Bind to Beta-lactamase, inactivate them and prevent the destruction Synergistic with other beta-lactams A. Clavulanic Acid – produced by S. Clavuligerul potentnt inhibitor of beta-lactamases (plasmid encoded) weak antibacterial action combined with Amoxicillin (Augmentin) or Ticarcillin( Timentin): the combination widens the antimicrobial spectrum B. Sulbactam Pivoxil and Ampicillin ( Unasyn) C. Tazobactam and Piperacillin (Tazocin) CARBAPENEMS - structurally related to Beta lactam antibiotics 1. Imipenem – gram (-) rods, gram (+) org. & anaerobes inactivated by dehydropeptidases in renal tubules resulting in low urinary concentration combined with Cilastatin ( dehydropeptidase inhibitor ) to reduce inactivation penetrates body tissues and fluids well including the CSF .25-0.5 g IV q 6-8 hrs Adverse effects include nausea, vomiting, diarrhea, reactions to infusion site; excessive in renal failure – seizures 2. Meropenem – slightly greater activity against gram (-) aerobes does not require an inhibitor penetrates CSF ERTAPENEM -Less active than meropenem or imipenem against Pseudomonas aeruginosa and acinetobacter species - It is not degraded by renal dehydropeptidase OTHER CELL WALL SYNTHESIS INHIBITORS 1. VANCOMYCIN Gram (+) staph Water soluble and quite stable MOA - Inhibits cell wall synthesis by binding firmly to D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide Resistance – modification of the D-Ala-D-Ala binding site of the peptidoglycan building block in which the terminal D-Ala is replaced by Dlactate resulting to loss of a critical H bond that facilitates high affinity binding of vancomycin to its target and loss of activity Synergistic with gentamicin and Streptomycin against E. faecium and E. faecalis strains that do not exhibit high levels of aminoglycoside resistance Poorly abosorbed from the GIT Administered orally for the treatment of antibiotic associated enterocolitis caused by C. difficile; 0.125 – 0.25 g q 6 hrs 99% excreted by glomerular filtration T1/2 6-10 days – not removed by dialysis Sepsis or endocarditits caused by Methicillin resistant staph Combined with Cefotaxime, Ceftriaxone or Rifampicin for the treatment of meningitis suspected or known to be caused by a highly penicillin resistant strain of pneumococcus. - Recommended dosage is 30 mg/kg/day in two or three divided doses - Adults with normal renal function – 1 g every 12 hrs Children – 40 mg/kg/d in 3 to 4 divided dose Causes phlebitis, chills and fever, ototoxicity, nephrotoxicity, red man or red neck syndrome - 2. FOSFOMYCIN - inhibits a very early stage of bacterial cell wall synthesis - inhibits cytoplasmic enzyme enol pyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the phosphoenolpyruvate to UDP-Nacetylglucosamine – 1st step in the formation of UDP-N- acetylmuramic acid, the precursor of acetylmuramic acid – found only in bacterial cell walls. - Drug is transported into the cell by glycerophosphate or glucose 6 phosphate transport systems - Resistance is due to inadequate transport of drug into the cell - Active against both Gram (+) and Gram (-) - In vitro synergism with beta lactams, aminoglycosides or fluoroquinolones - Available orally ( 2-4 g, single dose in uncomplicated UTI) and parenterally - Excreted through the kidneys - Safe in pregnancy 4. BACITRACIN - cyclic peptide mixture - active against Gram (+) organisms - inhibits cell wall formation by interfering with dephosphorylation - in cycling of the lipid carrier that transfers peptidoclycan subunits to the growing cell wall nephrotoxic - poorly absorbed; limited to topical use 500 units/g ointment + Polymyxin B or Neomycin 5. CYCLOSERINE - water soluble; very unstable at acid ph treat tuberculosis caused by M. tuberculosis resistant to first line agents - structural analogs of D-alanine and inhibits incorporation of D-alanine into peptidoglycan pentapeptide by inhibiting alanine racemase which converts L alanine to D alanine and Dalanyl- D-alanine ligase - widely distributed into tissues - excreted through the urine - 0.5 – 1 g /d in 2 – 3 divided doses - causes dose related CNS toxicity, headaches, tremors, acute psychocis, convulsions THANK YOU VERY MUCH AND STUDY WELL! PROTEIN SYNTHESIS INHIBITORS Ma. Shiela Cano-Guiking, M.D. The 30 S Inhibitors: I. AMINOGLYCOSIDES Older Aminoglycosides: Streptomycin Kanamycin Newer Aminoglycosides: Gentamicin Tobramycin Neomycin Amikacin Netilmicin Sisomicin Antimicrobial Spectrum: 1. Gram (-) Aerobic Bacilli 2. Beta-lactamase producers: Staph. aureus N. gonorrhea 3. Mycobacteria Mechanism of Action: - interferes with initiation complex of peptide formation - induces misreading of mRNA causing incorporation of incorrect AA causes breakup of polysomes into nonfunctional monosomes - Requires oxygen uptake, therefore ineffective against anaerobes. - Bactericidal Microbial Resistance: 1. enzyme inactivation 2. Cell surface alteration 3. receptor protein alteration 4. oxygen requirement related Kinetics: minimally absorbed from the GIT, well absorbed thru IM, IV poorly penetrate the BBB not significantly metabolized primarily executed unchanged through GF Clinical Uses: severe gram (-) rod infections Mycobacterial infections Toxicity: Ototoxicity (esp. with loop diuretics) Auditory damage – Neomycin, Kanamycin and Amikacin Vestibular Damage – Streptomycin, Gentamicin Nephrotoxicity (esp. with cephalosporins) Neomycin, Tobramycin, Gentamicin- most nephrotoxic STREPTOMYCIN - ribosomal resistance to this agent develops readily, limiting its role as a single agent - mainly used as a second line agent for treatment of tuberculosis - given at 0.5-1 g/d (7.5-15 mg/kg/day for children) IM or IV should be used only in combination with other agents to prevent emergence of resistance - In plague, tularemia and sometimes brucellosis, 1 g/d (15 mg/kg/day for children) IM or IV + oral tetracycline +Penicillin; effective for enterococcal endocarditis and 2 week therapy of viridans streptococcal endocarditis - Can cause fever, skin rashes and other allergic reactions, pain at injection site, vestibular dysfunction – most serious toxic effect If given during pregnancy, can cause deafness in the newborn GENTAMICIN employed mainly in severe infections (sepsis and pneumonia) caused by gram (-) bacteria in combination with a cephalosporin or a penicillin may be life saving given at 5-6 mg/kg/day IV in three equal doses + Penicillin G for bactericidal activity in endocarditis due to viridans streptococci or enterococci and in combination with Nafcillin in selected cases of staphylococcal endocarditis Serum concentrations and renal function should be monitored if administered for more than a few days or if renal function is changing (eg. Sepsis; often complicated by acute renal failure) Gentamicin sulfate 0.1% -0.3% cream, ointment – for the treatment of infected burns, wounds, or skin lesions and the prevention of intravenous catheter infections Topical gentamicin is partly inactivated by purulent exudates Ten milligrams can be injected subconjunctivally for treatment of ocular infections. Nephrotoxicity is reversible and usually mild; Irreversible ototoxicity manifested as vestibular dysfunction, hypersensitivity reactions are uncommon TOBRAMYCIN Antimicrobial spectrum and pharmacokinetic properties virtually identical to gentamicin Given at 5-6 mg/kg IM or IV into three equal amounts q 8 hours Blood levels should be monitored in renal insufficiency Slightly more active against pseudomonas but not E. faecium Ototoxic and nephrotoxic AMIKACIN semisynthetic derivative of kanamycin resistant to many inactivating enzymes for tuberculosis; given at 7.5 – 15 mg/kg/d as a once daily or 23x weekly Serum concentrations should be monitored Nephrotoxic and ototoxic NETILMICIN shares many characteristics with gentamicin and tobramycin dosage and the routes of administration are the same, completely therapeutically interchangeable with gentamicin or tobramycin and has similar toxicities KANAMYCIN AND NEOMYCIN Paromomycin is also a member of this group and all have similar properties Used for bowel preparation for elective surgery There is complete cross-resistance between kanamycin and neomycin Not significantly absorbed from the GIT; excretion of any absorbed drug is mainly through GF into the urine Too toxic for parenteral use, now limited to topical and oral use Solutions 1-5 mg/ml – used on infected surfaces or injected into joints, pleural cavity, tissue spaces or abscess cavities where infection is present (15 mg/kg/day) Ointments (Neomycin-Polymyxin-Bacitracin combination) applied to infected skin lesions or in the nares for suppression of staphylococci In preparation for elective bowel surgery, 1 g of Neomycin given orally q 6-8 hours + 1 g of erythromycin base; Paromomycin, 1 g q 6 hours orally for 2 weeks; effective in intestinal amoebiasis Sudden absorption of postoperatively instilled kanamycin from the peritoneal cavity (3-5 g) has resulted in curare-like neuromuscular blockade and respiratory arrest (Calcium gluconate and neostigmine can act as antidotes) Prolonged application to skin and eyes-severe allergic reactions SPECTINOMYCIN chemically related to the aminoglycosides binds at the 30 S subunit (bacteriostatic) Dispensed as the dihydrochloride pentahydrate for IM injection Used almost solely as an alternative treatment for gonorrhea in patients who are allergic to penicillin or whose gonococci are resistant to other drugs Single dose of 2 g ( 40 mg/kg ) II.TETRACYCLINES: Short Acting: Tetracyline, Oxytetracycline, Chlortetracycline Intermediate Acting: Demeclocycline, Methacycline Long Acting: Doxycycline, Minocycline Antimicrobial Spectrum: Rickettsia, V. cholera, M. pneumonia, Chlamydia, Shigella, H. pylori, P.tularensis, P. pseudomallei, Brucella, Psittacosis, Borrelia Minocycline – carrier state of Meningococcal infections, N. asteroides N. gonorrhea Mechanism of Action: - enter microorganisms in part by passive diffusion and in part by an energy dependent process of active transport binds to 30 S and prevents attachment of aminoacyl tRNA, prevents the addition of amino acids to the growing peptide Bacteriostatic Resistance: decreased intracellular accumulation due to impaired influx or increased efflux by an active transport protein pump ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome enzymatic inactivation Kinetics: limited CNS penetration absorption occurs mainly in the upper small intestine and is impaired by food ( except Doxycycline and Minocycline) Must not be taken with milk or antacids Cross placenta, excreted in milk Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half life of doxycycline Excreted mainly in bile and urine ( Doxycycline fecally eliminated; can be used in renal failure Clinical Uses: Borrelia burgdorfi (Lyme disease), Chlamydia, Ureaplasma, M. pneumonia, Rickettsia, Acne, Tularemia, Cholera, Leptospirosis, Protozoal infections Minocycline, 200 mg orally daily for 5 days, can eradicate the meningococcal carrier state Demeclocycline – inhibits the action of ADH in the renal tubule and has been used in the treatment of inappropriate secretion of ADH or similar peptides by certain tumors Tetracycline – 250-500 mg 4x/day adults 20-40 mg/kg/d – children above 8 y/0 600 mg daily dose for Demeclocycline and Methacycline 100 mg 1-2x/d for Doxycycline and Minocycline Toxicity: Renal toxicity, local tissue toxicity, photosensitization, GI distress, discolors teeth, inhibits bone growth in children, potentially teratogencic, hepatotoxicity, vestibular toxicity THE 50 S INHIBITORS: CHLORAMPHENICOL MACROLIDES CLINDAMYCIN/LINCOMYCIN STREPTOGRAMINS OXAZOLADINONES I CHLORAMPHENICOL Bactericidal – H. influenzae, N. meningitides, B. fragilis Bacteriostatic – S. epidermidis, S. aureus, , M. pneumonia, L. monocytogenes, diphtheria, L. multocida, Salmonella sp., Shigella sp., E. coli, Rickettsia, Anaerobes,ineffective for chlamydial infections Mechanism of Action: attaches at P sites of 50 S subunit of microbial ribosomes and inhibits functional attachment of amino-acyl end of AA-t-RNA to 50 S subunit inhibits peptidyl transferase step Spectrum: broad spectrum antibiotic more effective than Tetracyclines against Typhoid Fever and other Salmonella infections Kinetics: well absorbed after oral administration Chloramphenicol succinate used for parenteral administration is highly water soluble distributed into total body water excellent penetration into CSF, ocular and joint fluids rapidly excreted in urine, 10% as chloramphenicol; 90% as glucuronide conjugate systemic dosage need not be altered in renal insufficiency but must be reduced markedly in hepatic failure Newborns less than a week old and premature infants also clear Chloramphenicol less well, dosage should be reduced at 25 mg/kg/d Uses: meningitis, rickettsia, Salmonella and anaerobic infections ineffective against chlamydial infections occasionally used topically in the treatment of eye infections for its well penetration to ocular tissues and the aqeous humor Adverse Effects: GIT, oral or vaginal candidiasis, irreversible aplastic anemia, reversible bone marrow depression, Gray Baby Syndrome II. MACROLIDES: Old Generation: Erythromycin, Oleandomycin, Troleandomycin, Spiramycin, Josamycin New Generation: Rosaramycin, Roxithromycin, Clarithromycin, Azithromycin, Dirithromycin Mechanism of Action: binds to the P site of the 50 S bacterial ribosomal subunit. Aminoacyl translocation and formation of initiation complex are blocked Inhibitory or bactericidal RESISTANCE: reduced permeability of the cell membrane or active efflux production (by Enterobacteriaceae) of esterases that hydrolyze macrolides modification of the ribosomal binding site by chromosomal mutation Spectrum: Erythromycin has a narrow Gram (+) spectrum similar to Pen. G. Also active against Chlamydia and Legionella organisms 1. Erythromycin: prototype distributed into total body water poor CSF penetration food interferes with absorption serum half life is app. 1.5 h normally and 5 hours in patients with anuria not removed by dialysis metabolized in the liver traverses the placenta and reaches the fetus Commercial Preparations: Oral-stearate, ethyl succinate, estolate salts – 250-500 mg q 6 h adults 40 mg/kg/d - children Parenteral- lactobionate, gluceptate – 0.5-1 g q 6 hours for adults 20-40 mg/kg/d for children Adverse Effects: GIT dysfunction, intrahepatic cholestatic jaundice - Erythromycin metabolites can inhibit cytochrome p450 enzymes and thus increase the serum concentrations of theophylline, oral anticoagulants, cyclosporine and methylprednisolone;also oral digoxin by increasing its bioavailability 2. Clarithromycin - hydroxylated derivative of erythromycin - more active against Gram (+) pathogens, Legionella and Chlamydia than Erythromycin - lower frequency of GIT effects, less frequent dosing - Half life of 6 hours - given at 250-500 mg twice daily 3.Azithromycin - more active than erythromycin against several Gram (-) pathogens - maintains high concentrations for prolonged periods into a number of tissues (lungs, tonsil, cervix) - tissue half life – 2-4 days - long half-life allows once daily oral administration and shortening of treatment in many cases ( a single 1 g dose of azithromycin is as effective as a 7 day course of doxycycline for chlamydial cervicitis and urethritis) -Community acquired pneumonia – 500 mg loading dose, followed by a 250 mg - single daily dose for the next 4 days -Should be administered 1 hour before or 2 hours after meals; aluminum and magnesium delay absorption and reduce peak serum concentrations Does not inactivate cytochrome p450 enzymes and free of the drug interactions that occur with erythromycin and clarithromycin AZITHROMYCIN KETOLIDES - semisynthetic 14 membered ring macrolides Telithromycin – active in vitro against S pyogenes, S. penumoniae, S. aureus, H. influenzae, Moraxella catarrhalis, mycopasmas, legionella sp, chlamydia sp, Helicobacter pylori, N. gonorrhoaea, B. fragilis, T gondii and nontuberculosis mycobacteria -Oral bioavailability – 57% - good tissue and intracellular penetration - metabolized in the liver - eliminated by a combination of biliary and urinary routes of excretion - administered as a once daily dose of 800 mg - indicated for treatment of respiratory tract infections, including community acquired bacterial pneumonia, acute exacerbations of chronic bronchitis, sinusitis and streptococcal pharyngitis - a reversible inhibitor of the CYP3A4 enzyme system TELITHROMYCIN III. CLINDAMYCIN/LINCOMYCIN Mechanism of Action: attach to 50 S ribosomal subunit, inhibits protein synthesis by interfering with the formation of initiation complexes and translocation reaction Spectrum: Narrow Gram (+) spectrum, excellent activity against anaerobic bacteria; strep, pneumococci, staphylococci Resistance: mutation of the ribosomal receptor site modification of the receptor by a constitutively expressed methylase enzymatic inactivation Clindamycin is more clinically used than Lincomycin: excellent absorption given at 150-300 mg q 6 hrs – adults; 10-20 mg/kg/d for children low concentration in CSF well bone penetration excreted mainly via the liver, bile and urine half life is 2.5 hours normally and 6 hours in patients with anuria more toxic than erythromycin prophylaxis of endocarditis in patients with valvular heart disease for dental procedures most important indication is the treatment of severe anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections + aminoglycoside or cephalosporin used to treat penetrating wounds of the abdomen and the gut Septic abortion, pelvic abscesses, aspiration pneumonia + primaquine – effective alternative to trimethoprim sulfamethoxazole for moderate to moderately severe Pneumocystis carinii pneumonia in AIDS patients + Pyrimethamine for AIDS – related toxoplasmosis of the brain ADVERSE EFFECTS: Diarrhea, nausea, skin rashes, impaired liver function and neutropenia; Antibiotic associated colitis caused by toxigenic C. difficile NEWER AGENTS: STREPTOGRAMINS: Quinuprisitn-Dalfopristin (Synercid) action is similar to macrolides except bactericidal for staph and most organisms except Enterococcus faecium prolonged postantibiotic effect up to 10 h for Staph. aureus administered IV at 7.5 mg/kg q 8-12 h eliminated through fecal route, < 20% urine inhibits CYP 3A4, which metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, nonnucleoside reverse transcriptase inhibitors and cyclosporine. Clinical Uses: infections caused by Vancomycin resistant strains of E faecium but not E. faecalis, bacteremis or respiratory tract infections caused by methicillin-resistant staphylococci and penicllin susceptibe and resistant strains of S. pheumonia Toxicities: infusion related events, pain at the injection site, arthralgia, myalgia synd STREPTOGRAMIN A STREPTOGRAMIN B OXAZOLADINONES: Linezolid (Zyvox) inhibits protein synthesis by preventing formation of the ribosome complex that initiated protein synthesis. Its unique binding site located on 23 S ribosomal RNA of the 50 S subunit, results in no cross resistance with other drug classes Has high oral bioavailability, half life of 4-6 h Uses : staph, strep, enterococci, G(+) anaerobic cocci, G (+) rods, Corynebacterium, L. monocytogenes - treatment of infections caused by vancomycin resistant E. faecium and other infections caused by multiple drug resistant organisms METABOLIC INHIBITORS: SULFONAMIDES - structurally similar to p-aminobenzoic acid (PABA) that competitively inhibits dihydropteroate synthase - inhibits growth by reversibly blocking folic acid synthesis - mammalian cells do not make folic acid and are not affected - cross the placenta and secreted in breast milk and should not be given to pregnant Women - highly bound to plasma proteins esp, albumin - penetrates CNS well SPECTRUM: - Gram (+) & Gram (-) Bacteria - Nocardia - C. trachomatis - Enteric bacteria (E. coli, Klebsiella, Salmonella, Shigella Enterobacter) Ricketssia – sulfonamides do not inhibit these organisms but stimulate its growth Resistance: - occurs as a result of mutations that: 1. cause overproduction of PABA 2. cause production of a folic acid synthesizing enzyme that has a low affinity for Sulfonamides 3. cause a loss of permeability to the sulfonamides Pharmacokinetics: - 3 MAJOR GROUPS: 1. ORAL, ABSORBABLE 2. ORAL, NON-ABSORBABLE 3. TOPICAL Intravenous Preparation: - Na salts of sulfonamides in D5W Oral, absorbable sulfonamides: DRUGS HALF LIFE ORAL ABS Short Short (6 h) Short (9 h) Prompt (peaks in 1-4h) Prompt Prompt Intermediate(10-17h) Intermediate (10-12h) No data Slow (peak in 4-8h) Slow Slow Long (7-9 days) Intermediate 1.short acting Sulfacytine Sulfisoxazole Sulfamethizole 2. Medium acting Sulfadiazine Sulfamethoxazole Sulfapyridine Long Acting Sulfadoxine absorbed from stomach and small intestine - distributed widely to tissues and body fluids (CSF), placenta and fetus - protein binding 20% to over 90% - therapeutic concentration – 40-100 ug/ml of blood - peak blood levels – 2h to 6 h after oral ingestion - metabolism: glucoronidation or acetylation in liver - eliminated in urine-mainly by glomerular filtration CLINICAL USES: 1. Urinary tract infection Sulfisoxazole – 1 gm 4x daily }combined with PHENAZOPYRIDINE Sulfamethoxazole – 1 g 2-3 x daily } (U.T. anesthetic) 2. Respiratory infections 3. Sinusitis, bronchitis, pneumonia 4. Otitis media 5. Dysentery 6. Acute Toxoplasmosis Sulfadiazine + Pyrimethamine – Synergistic Block sequential steps in folate synthesis: Sulfadizine- inhibits dihydropteroate synthase Pyrimethamine – inhibits dihydrofolate reductase Dosage – Sulfadiazine – 1 g 4x daily Sulfadiazine + pyrimethamine – 75 mg loading dose ffd by 25 mg OD Folinic Acid – administered to minimize bone marrow suppression 7. Malaria - sulfadoxine + pyrimethamine – 2nd line agent in the treatment for malaria ORAL, NONABSORBABLE AGENTS Sulfasalazine (Salicylazosulfapyridine) more effective than soluble sulfonamides or other antimicrobials taken orally in inflammatory bowel disease ulcerative colitis enteritis other inflammatory bowel disease split by intestinal microflora to yield: Sulfapyridine – absorbed and may lead to toxic symptoms If more than 4 g of sulfasalazine is taken per day esp. in persons who are slow acetylators 5-aminosalicylate (5-ASA) – released in the colon in high concentrations and is responsible for an anti-inflammatory effect TOPICAL AGENTS: Sodium Sulfacetamide ophthalmic solution or ointment effective for bacterial conjunctivitis adjunct therapy for trachoma Mafenide acetate used topically to prevent bacterial colonization and infection of burn wounds inhibits also carbonic anhydrase – cause metabolic acidosis Silver Sulfadiazine less toxic topical sulfonamide preferred to mafenide for prevention of infection of burn woulds ADVERSE REACTIONS: Cross allergy with the ffg. carbonic anhydrase inhibitors, thiazides, furosemide, bumetanide, furosemide, diazoxide, sulfonylureas, hypoglycemics Most common adverse effects: Fever, skin rashes, exfoliative dermatitis, nausea, vomiting, urticaria, photosensitivity Urinary tract disturbances: sulfas may ppt. in urine at neutral or acid phCrystalluria – treated with sod. Bicarbonate to alkalinize urine and fluids to maintain adequate hydration Hematuria Obstruction implicated in nephrosis and allergic nephritis OTHER SIDE EFFECTS: Stevens-Johnson Syndrome – uncommon but serious and potentially fatal type of skin & mucous membrane eruptions Hematopoietic disturbances: hemolytic or aplastic anemia, thrombocytopenia, granulocytopenia, leukemoid reaction, provoke hemolytic reactions in patients with deficient rbc glucose 6 phosphate dehydrogenase increased risk of kernicterus in newborns when sulfonamides were taken near the end of pregnancy Stomatitis, Conjunctivitis, Arthritis, Hepatitis Polyarteritis nodosa – rare Psychosis – rare STEVENS JOHNSON SYNDROME TOXIC EPIDERMAL NECROLYSIS TRIMETHOPRIM well absorbed from the gut widely distributed in body fluids and tissues incldg. CSF found in high concentrations in prostatic & vaginal fluids Even if given orally alone or in combination with sulfonamides, it will have the same half-life More lipid soluble – larger volume of distribution than sulfonamides RESISTANCE TO TM: due to reduced cell permeability due to overproduction of dihydrofolate reductase due to production of an altered reductase & reduced drug binding CLINICAL USES: Oral TM: acute UTI 100 mg BID community acquired organisms – 200 ug to 600 ug/ml concentration of TM in urine ADVERSE EFFECTS: megaloblastic anemia, leucopenia, granulocytopenia Prevention of adverse effects: simultaneous administration of folinic acid 6 mg-8 mg/day TRIMETHOPRIM-SULFAMETHOXAZOLE (COTRIMOXAZOLE) synergistically active antimicrobial agent which blocks two sequential steps in the obligate enzymatic reaction in bacteria preventing the formation of nucleotides: Sulfamethoxazole – competitively inhibits the incorporation of PABA into folic acid Trimethoprim inhibits dihydrofolate reductase preventing the reduction of dihydrofolate to tetrahydrofolate ADVANTAGES OF THE COMBINATION: increased potency increases spectrum decreased incidence of resistance exhibits selective toxicity for bacteria which must synthesize their own folic acid Trimethoprim is more potent, more lipid soluble and has a greater volume of distribution than sulfa drugs Penetrates CSF well 65-70% of each drug is protein bound Eliminated in the urine within 24 h – reduce dose by half if creatinine clearance is 15-30 ml/min CLINICAL USES: Oral TMP-SMX urinary tract infection: complicated UTI – 2 double strength tabs (TM-160 mg+SM 800 mg) q 12 hours Recurrent UTI prophylaxis – ½ of regular size (single strength) 3x weekly Prostatitis – 2 double strength tabs (TM 160 mg + SM 800 mg) q 12 h Susceptible strains of shigella and salmonella 2 double strength tabs q 12 h Children with shigellosis, UTI, otitis media-8mg/kg TM and 40 mg/kg SM q 12 hours P. carinii and other pathogens – orally 15-20 mg/kg in immunosuppressed patients – one double strength tab daily or 3x weekly Nontuberculous mycobacterial infection Respiratory tract pathogens – useful alternative to B lactamase for community acquired bacterial pneumonia CLINICAL USES: Inravenous TMP-SMX: drug of choice for moderately severe to severe pneumocystis pneumonia esp. patients with AIDS TM 80 mgs + SM 400mg/5 ml diluted in 125 ml of D5W Folinic acid increases morbidity and treatment failures so not used Used for Gram (-) bacterial sepsis – incldg. Those caused by some multiple drug resistant species such as Enterobacter and Serratia Shigellosis Typhoid fever UTI caused by susceptible organisms if patient is unable to take drug orally Dosage- 10-20 mg/kg/day of TM component Oral Pyrimethamine + Sulfadiazine= used in the treatment of leishmaniasis and toxoplasmosis Pyrimethamine + Sulfadoxine = used in the treatment of Falciparum malaria ADVERSE EFFECTS: mostly due to untoward reactions to SMX dermatological effects GI effects: glossitis, stomatitis, nausea and vomiting CNS disturbances: headache, depression, hallucinations Hematologic reactions- aplastic, hemolytic and macrocytic anemia, coagulation disorders Vasculitis Renal impairment or damage AIDS PATIENTS more sensitive to increased frequency of reactions toward TMPSMX drug: -rashes, hemtologic effects-leukopenia, fever, diarrhea, elevated hepatic aminotransterases, hyperkalemia, hyponatremia FLUOROQUINOLONES QUINOLONES synthetic fluorinated analogs of nalidixic acid block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA Gyrase) and topoisomerase IV INHIBITION OF DNA GYRASE prevents relaxation of positively supercoiled DNA that is required for normal transcription and replication INHIBITION OF TOPOISOMERASE IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division EARLY QUINOLONES (Nalidixic Acid, Oxolinic acid, Cinoxacin) did not achieve systemic antibacterial levels useful only for treatment of lower UTI ANTIBACTERIAL ACTIVITY: Gram (-) aerobic bacteria- excellent activity Gram (+) organism – limited activity NORFLOXACIN – least active against gm (+) and Gm (-) SECOND GROUP excellent gm (-) activity, moderate gm (+) activity Ciprofloxacin (prototype), Enoxacin, Lomefloxacin, Levofloxacin, Ofloxacin, Pefloxacin Methicillin susceptible S. aureus – susceptible to fluoroquinolones Methicillin resistant S. aureus – resistant to fluoroquinolones Ciprofloxacin – most active against gm (-) expecially P. aeroginosa Levofloxacin – 2x more potent than ofloxacin superior activity against gm (+) org. incldg S. pneumoniae THIRD GROUP: improved activity against gm (+) organism particularly S. pneumoniae and some staph Clinafloxacin – best activity against gm (+) activity Gatifloxacin Sparfloxacin – some activity against anaerobes not as active as ciprofloxacin against gm (-) FOURTH GROUP enhanced gm (+) activity good activity against anaerobic bacteria Moxifloxacin, Trovafloxacin Other activities: Atypical pneumoniae ( Mycoplasma, Chlamydia Intracellular pathoges (Legionella, Mycobacteria tb, and M. avium complex) RESISTANCE: Due to one or more point mutations in the quinolone binding region of the target enzyme Due to a change in the permeability of the organism DNA GYRASE – primary target in E. coli with single step mutants exhibiting amino acid substitution in the alpha subunit of the gyrase TOPOISOMERASE IV – secondary target in E. coli that is alerted in mutants expressing higher levels of resistance IN STAPH AND STREP Topoisomase IV – primary target DNA gyrase – secondary target cross resistance to other members PHARMACOKINTEICS: well absorbed after oral intake bioavailability 80-95% distributed widely in body fluids and tissues Half life 3 hrs- norfloxacin and ciprofloxacin 10 hrs. – pefloxacin & Fleroxacin > 10 hrs. – sparfloxacin Long half life : Levofloxacin, moxifloxacin, sparfloxacin, trovafloxacin Ofloxacin and Levofloxacin – identical pharmacokinetics Oral absorption impaired by divalent cations including those antacinds Alatrovafloxacin – inactive prodrug of trovafloxacin for parenteral administration Concentration is higher in prostate, kidney, neutrophiles and macrophages than in serum ELIMINATION: Renal – tubular secretion, Glomerular filtration - If creatinine clearance < 50%ml/min – adjust dosage Sparfloxacin – a50 % fecal, 50% renal If creatinine clearance <50 ml/min -400 mg LD followed by 200 mg q other day Non renal – trovafloxacin and moxifloxacin _ CI in patients with hepatic failure CLINICAL USES: UTI – even when caused by multi drug resistant bacteria like pseudomonas Norfloxacin 400 mg Bid Ciprofloxacin 500 mg BID Ofloxacin 400 mg BID Prostatitis – 4-6 wks Norfloxacin, Ciprofloxacin, Ofloxacin Bacterial Diarrhea Shigella, Salmonella, toxigenic E. coli, campylobacter Infection of soft tissues, bones, joints, intraabdomina and respiratory tract infection even caused by Pseudomonas and Enterobacter Gonococcal infection, including disseminated disease Ciprofloxacin, ofloxacin oral single dose Chlamydia urethritis or cervicitis ofloxacin x 7 days Legionellosis Ciprobay – 2nd line agent TB and atypical mycobacteria infection Eradication of meningococci carrier Prophylaxis in neutropenic patient Upper and lower RTI Newer fluoroquinolones enhanced gm (+) activity and atypical pneumonia ADVERSE EFFECTS: most common – nausea, vomiting and diarrhea Others – headache, dizziness, insomnia, skin rash, abn liver function test Trovafloxacin – associated rarely with acute hepatitis and hepatic failure Photosensitivity – lomefloxacin, pefloxacin CV toxicity – Grepafloxacin Damage growing cartilage and cause arthrpathy- not recommended < 18 y/o Tendinitis – may rupture DRUG INTERACTION: Theophylline – increase metabolism of theophylline – elevated concentration-seizures CONTRAINDICATIONS: Nursing mothers, children, pregnancy NALIDIXIC ACID First antibacterial quinolone introduced in 1963 Not fluorinated Very rapid elimination, no systemic bacterial effects Used only for UTI Oxolinic Acid and Cinoxacin – similar structure NOVOBIOCIN: Acidic antibiotic prod. By Streptococcus niveius Inhibitor of B subunit of DNA gyrase Active mainly against gm (+) bacteria Rapid emergence of resistance; inc. incidence of adverse effects No clear indication URINARY ANTISEPTICS: Methenamine Mandelate and Hippurate releases mandelic acid, hippuric acid or formaldehyde in sufficiently acidic urine bactericidal or bacteriostatic to most organisms causing UTI except Proteus Nalidixic Acid and Cinoxacin: interferes with DNA polymerization by binding to DNA gyrase causes nausea, vomiting, skin rashes and CNS effects Nitrofurantoin well absorbed after ingestion excreted into the urine 100 mg q 6 h with food or milk contraindicated in severe renal insufficiency bactericidal or bacteriostatic for many gram (+) and gram (-) antagonizes the action of nalidixic acid causes hypersensitivity, nausea, vomiting, neuropathies and hemolytic anemia in G6PD Trimethoprim selective inhibition of bacterial dihydrofolate reductase may be bacteriostatic or bacteridial + Sulfamethoxazole – P. carinii, shigellosis, prostatitis, some nontuberculous mycobacterial infections, systemic salmonella infections, complicated UTI MISCELLANEOUS ANTIBACTERIAL DRUGS: Metronidazole penetrates CSF, metabolism-liver treatment of amoebic infections, intraabdominal infections, vaginitis, antibiotic associate enterocolitis, brain abscess oral, IV, rectal suppository causes metallic taste, glossitis and anorexia Polymyxin B group of basic peptides active against Gram (-), bactericidal treatment of serious enteric infections(Pathogenic E. coli, Shigella, Enterobacter, Klebsiella and Pseudomonas , not Proteus) poor tissue distribution attach to and disrupt bacterial cell membrane, bind and inactivate endotoxin toxicity includes neurological and renal effects topical (+Bacitracin+Neomycin) Mupirocin ointment for topical application active against staph aureus; inh. Isoleucyl tRNA synthetase indicated for impetigo, intranasal application for elimination of methicillin resistant S. aureus carriage by patient or health care workers