抗生素概论 review of antibiotics part 1课件

Review of Antibiotics Part 1,Gary R. Skankey, MD, FACP, FIDSA University of Nevada School of Medicine,Penicillin - Spectrum,Lancfield group streptococci Alpha streptococcus, except pneumococcus Enterococcus Oral anaerobes - peptostreptococcus, etc. Treponema pallidum and other spirochetes Actinomyces,Penicillin - Mechanism of Action,Penicillin is a beta-lactam antibiotic Binds to penicillin binding proteins on bacterial cell surface Inhibits cell wall synthesis,Penicillin and Pneumococcus,About 30% resistant, 15% intermediately sensitive Altered PBPs makes penicillin and sometimes cephalosporins ineffective Plasmid mediated,possibly transferred from other species Plasmid also caries resistance genes to other antibiotics: macrolides, tetracyclines, sulfa drugs,Penicillin - Neisseria,Increasing resistance due to beta-lactamase production in N. gonnorrhea and N. meningitidis Unless organism proven sensitive, do not use penicillin empirically for meningitis or sexually transmitted disease.,Penicillin - Dosing,Mild infections - cellulitis, pharyngitis, etc., Penicillin V 500mg PO QID Penicillin G 1 - 2 million units IV Q4hrs Serious infections - meningitis, endocarditis Penicillin G 4 million units IV Q4hrs. Syphillis latent: 2.4 million units benzathine penicillin IM Q week x 3 weeks neurosyphillis: 4 million units IV Q4hrs x 10 days Adjust dose for renal failure,Penicillin - Clinical Uses,Syphillis S. pyogenes pharyngitis Actinomyces infections Subacute bacterial endocarditis due to pcn-sensitive alpha-streptococci Pencillin-sensitive pneumococcal and meningococcal meningitis,Ampicillin - Spectrum,Same gram positives as penicillin Enteric gram negatives (if sensitive): E. coli Proteus Salmonella Shigella Respiratory tract gram negatives Haemophillus influenzae, Moraxella morganii Pasteurella moltocida Listeria monocytogenes,Ampicillin and Enteroccocus,Weak affinity for penicillin-binding proteins bacterostatic Must add aminoglycoside (gentamicin) to create bacterocidal regimen E. faecalis usually sensitive E. faecium usually resistant,Ampicillin and Haemophillus,About 40% of H. influenzae is resistant Produces beta-lactamase Resistance overcome by use of beta-lactamase inhibitor,Ampicillin and Salmonella,Increasing resistance in salmonella makes it unreliable against typhoid fever. About 40% resistance,Ampicillin - Dosing,Mild infections - cystitis, pharyngitis Amoxacillin 500 mg PO TID Moderate infections - pyelonephritis, cellulitis, osteomyelitis Ampicillin 1 - 2 gm IV Q6hrs Severe infections - meningitis, endocarditis Ampicillin 2 gm IV Q4hrs Adjust dose for renal failure,Ampicillin - Clinical Uses,Amoxacillin for ampicillin-sensitive UTIs In combo with gentamicin for enterococcal endocarditis Listeria monocytogenes infections meningitis bacteremia Cat bite cellulitis + clindamycin Penicillin-sensitive alpha-streptococcal SBE,S. aureus - beta lactamase,1st described in 1945 Confers resistance to penicillin and ampicillin Coded for on plasmid Plasmids also carry resistance to other antibiotics Usually inducible,Beta-lactamase-Resistant Penicillins,Methicillin high risk of interstitial nephritis, no longer on market Nafcillin Oxacillin Dicloxacillin (PO),Nafcillin/Oxacillin - Spectrum,Oxacillin-sensitive S. aureas Oxacillin-sensitive coagulase negative staph Okay against Lancfield group streptococci and viridans streptococci, but there are better drugs for these No gram negative or anaerobic coverage to speak of,Nafcillin/Oxacillin - Pearls,Most potent anti-staph drug made Excellent CNS penetration (staph meningitis) No dose adjustment for renal failure predominantly hepatic excretion Watch out for: leukopenia thrombocytopenia interstitial nephritis,Nafcillin/Oxacillin - Clinical Uses,All MSSA infections: Endocarditis Meningitis Osteomyelitis Pneumonia Abscesses Cellulitis,Anti-pseudomonal Penicillins,Carbenicillin no longer on the market Ticarcillin only on market as Timentin Piperacillin hard to get as piperacillin alone, usually only available as Zosyn,Piperacillin - Spectrum,Pseudomonas Enterobacteriacae group Beta-lactamase negative Moraxella, Neisseria, Haemophillus Same gram positive spectrum as penicillin Same anaerobic spectrum as penicillin,Piperacillin dosing,Mild to moderate gram negative (non-pseudomonal) or streptococcal infections 3 gm IV Q6 hrs. Moderate to severe pseudomonal infections 3 gm IV Q4 hrs. Or Piperacillin/tazobactam 3.375 gm IV Q4 hrs,Beta-lactam/Beta-lactamase Inhibitor Combinations,Unasyn ampicillin/sulbactam Timentin ticarcillin/clavulenate Zosyn piperacillin/tazobactam,Unasyn - Spectrum,Streptococci MSSA All anaerobes Beta-lactamase-producing gram negatives Enterococcus - bacterostatic Penicillin-sensitive pneumococcus,Unasyn - Dosing,Mild infections 1.5 gm IV Q6 hrs. Moderate to severe infections 3.0 gm IV Q6 hrs. Adjust dose for renal failure,Unasyn - Clinical Uses,Head and neck infections Peritonsilar abscess Sinusitis Mastoiditis Mandibular osteomyelitis Actinomyocosis Infected Bite Wounds Human Dog Cat Diabetic Foot infections, including osteomyelitis Culture negative endocarditis,Zosyn - Spectrum,Streptococci MSSA All anaerobes Beta-lactamase-producing gram negatives Enterococcus - bacterostatic Piperacillin-sensitive pseudomonas 18 gm per 24 hrs,Zosyn - Dosing,Usual dosing 3.375 gm IV Q6 hrs. Fulminant sepsis 4.5 gm IV Q6 hrs. Pseudomonas sepsis 3.375 gm IV Q4 hrs Adjust dose for renal failure,Zosyn - Clinical Uses,Intra-abdominal infections Nosocomial aspiration pneumonia Diabetic foot infections when Pseudomonas might be involved Pulmonary infections in patients with bronchiectasis or cystic fibrosis,Cephalosporins,Inhibit cell wall synthesis - peptidoglycan Side effects are mild rash eosinophilia leukopenia leukocytosis biliary sludge (ceftriaxone) thromobocytosis,First Generation Cephalosporins,Cefazolin - Ancef IV Cephalothin - Keflin IV Cephalexin - Keflex PO Cephradine - Velosef PO Cefadroxil - Duricef PO,Ancef - Spectrum,Staphylococcus Streptococcus E. coli, Proteus, Klebsiella if sensitive,Ancef - Clinical Uses,Any MSSA infection Cellulitis (2 gm IV Q8 hrs.) Osteomyelitis Endocarditis Pneumonia Not for meningitis Any Lancfield or viridans group streptococcal infections Endocarditis Cellulitis Sensitive enteric gram negative infections UTI,Second Generation Cephalosporins,Cefuroxime IV - Zinacef Cefotetan IV - Cefotan Cefoxitin IV - Mefoxin Cefuroxime axitil PO - Ceftin Cefaclor PO - Ceclor Cefprozil PO - Cefzil,Cefuroxime/Cefotetan - Spectrum,H. influenzae Anaerobes Staphylococcus Streptococcus Enterobacteriaceae,1st vs 2nd Generation,1ST GENERATION H. influenzae - S. aureus + Streptococcus + Moraxella - Gram negatives + Anaerobes -,2ND GENERATION H. influenzae + S. aureus + Streptococcus + Moraxella + Gram negatives + Anaerobes +,Cefuroxime - Clinical Uses,Upper respiratory tract infections sinusitis peritonsilar abscess otitis media etc., Lower respiratory tract infections pneumonia acute bacterial bronchitis Urinary tract infection,Cefotetan/Cefoxitin - Clinical Uses,Intra-abdominal infections diverticulitis intra-abdominal abscess peritonitis cholycystitis etc., Osteomyelitis Diabetic foot infections,Third Generation Cephalosporins,Cefotaxime IV - Claforan Ceftriaxone IV - Rocephin Ceftazidime IV - Fortaz Cefixime PO - Suprax Cefpodoxime PO - Vantin,Claforan/Rocephin - Spectrum,Streptococci Viridans, Lancfield groups, pneumococcus S. aureus Enteric gram negatives H. influenzae Neisseria meningitidis and gonnorrhea some anaerobes,Fortaz - Spectrum,All gram negatives, including Pseudomonas Weak if any gram positive coverage No anaerobic coverage,Claforan/Rocephin - Clinical Uses,Meningitis - 2gm Q4 hrs/2gm Q12 hrs Community-acquired pneumonia UTI Upper Respiratory Tract Infections sinusitis peritonsilar abscess Intra-abdominal infections,Fortaz - Clinical Uses,Hospital-acquired pneumonia Hospital-acquired UTI Post-op meningitis Intra-abdominal infections Pulmonary infections in patients with cystic fibrosis or bronchiectasis Nail-puncture cellulitis/osteomyelitis,Fourth Generation Cephalosporin,Cefepime IV - Maxipime,+,N,S,HCI H2N,N,H N,O,OCH3,H,H,O,N,S,COOH,N,CH3, H2O,cefepime,CI-,ZWITTERIONIC CHEMICAL STRUCTURE,*Bcher K et al. J Antimicrob Chemother. 1992;30:365-375.,CEFEPIME GASTROINTESTINAL PENETRATION,Cefepime pharmacokinetics and effects on fecal flora were assessed in 8 healthy volunteers who received 1 g q12h IV for 8 days* Elimination was almost entirely renal, with no evidence of accumulation Minimal changes in intestinal flora (16 genera analyzed),GRAM-NEGATIVE IN VITRO* ACTIVITY OF CEFEPIME,*In vitro activity does not necessarily correlate with clinical results. Cefepime has been shown to be active against susceptible strains of these pathogens in clinical infections. Including -lactamaseproducing strains.,Acinetobacter calcoaceticus subsp lwoffi Citrobacter diversus Citrobacter freundii Enterobacter spp Enterobacter agglomerans Escherichia coli Haemophilus influenzae Hafnia alvei Klebsiella oxytoca,Klebsiella pneumoniae Moraxella catarrhalis Morganella morganii Proteus mirabilis Proteus vulgaris Providencia rettgeri Providencia stuartii Pseudomonas aeruginosa Serratia marcescens,*In vitro activity does not necessarily correlate with clinical results. Cefepime has been shown to be active against susceptible strains of these pathogens in clinical infections.,GRAM-POSITIVE IN VITRO* ACTIVITY OF CEFEPIME,Staphylococcus aureus (methicillin-susceptible only) Staphylococcus epidermidis (methicillin-susceptible only) Staphylococcus saprophyticus Streptococcus agalactiae (Lancefield group B streptococci) Streptococcus pneumoniae Streptococcus pyogenes (Lancefield group A streptococci) Viridans group streptococci,Maxipime - Clinical Uses,Hospital-acquired pneumonia Sepsis in prolonged hospitalization Intra-abdominal infections,Cephalosporins,Carbipenems,Imipenem - Primaxin Meropenem Merem Ertapenem Invanz Doripenem - Dorimax Inhibit cell wall synthesis,Primaxin/Merem/Dorimax - Antibacterial Spectrum,Covers everything but: MRSA Stenotrophomonas B. cepacia pcn-resistant enterococcus (only bacterostatic vs.pcn.sensitive strains) C. difficile some pcn-resistant pneumococcus,Imipenem - Primaxin Toxicity,Rash - 50% cross-allergenicity with penicillin Seizures renal failure (high serum levels) intracranial pathology (lowers seizure threshold) Nausea/vomiting Leukocytosis Thrombocytopenia,Merem - Toxicity,Same as Primaxin, except Minimal seizure risk,Ertapenem spectrum,All gram positives (except MRSA, and vanco-resistant Enterococcus faecium) All gram negatives (except pseudomonas) All anaerobes,Vancomycin,Vancomycin,Class - glycopeptide Inhibits cell wall synthesis, and RNA synthesis (double action) Binds to d-ananyl-d-alanine portion of cell wall precursor,Vancomycin - Toxicity,Red mans syndrome histamine release during too rapid infusion Ototoxicity commonly irreversible associated with sustained high doses (peaks 30) Nephrotoxicity very uncommon now ototoxicity and nephrotoxicity amplified in presence of aminoglycoside or high-ceiling diuretics,Vancomycin - Dosing,Generally 1 gm IV Q12hrs Peak and trough with third or fourth dose Target peak 30 - 40 ug/dl Target trough 10 - 15 ug/dl (mild to moderate infections) Target trough 15 20 ug/dl (more severe infections or those with penetration issues) If trough high lengthen interval If peak high or low adjust dose,Vancomycin - Dosing,Vancomycin - Dosing Random Levels,Use only when patients serum creatinine is unstable Write order to give dose as soon as random level result known Vancomycin 1 gm IV Q24 hrs prn random level 10 or 12 Never order when patient receiving regularly dosed Vancomycin,Trimethoprim/Sulfamethoxazole,Each component inhibits sequential steps of tetrahydrofolic acid synthesis thus act synergistically High oral bioavailablilty,Trimethoprim/Sulfamethoxazole,Toxicity 75% adverse reactions involve skin urticarial rash most common Stevens-Johnson Syndrome, exfoliative dermatitis, toxic epidermal necrolysis are rare allergic cholestatic hepatitis reversible drop in creatinine clearance in patients with normal renal function irreversable renal failure in patients with renal disease,Uses of Trimethoprim/Sulfamethoxazole,Useful alone or in combo with Rifampin in mild MRSA infections UTI, Bronchitis, cellulitis Switch to PO TMP/SMX after a course of IV vancomycin Use in combination with vancomycin and rifampin in serious MRSA infections Drug of choice for Stenotrophomonas maltophilia Drug of choice for Pneumocystis,Rifampin,Inhibits DNA-dependent RNA polymerase Concentration in lung exceeds serum levels PO = IV Synergy demonstrated with cefazolin vs MSSA and with Vancomycin vs MRSA Never use as monotherapy, resistance develops rapidly,Rifampin - Toxicity,Chemical hepatitis GI intolerance Increase serum creatinine,Rifampin - Drug-Drug Interactions,Increases hepatic metabolism of many drugs thus reducing their serum levels: coumadin theophyline fluconazole, itraconazole, ketoconazole digoxin cyclosporin propranolol sulfonylureas prednisone dilantin,Synercid - quinupristin,Synercid - dalfopristin,Synercid,Class : Streptogramin Quinupristin and dalfopristin act synergistically Me