1、Review of AntibioticsPart 1Gary R.Skankey,MD,FACP,FIDSAUniversity of NevadaSchool of MedicinePenicillin-Spectrum Lancfield group streptococci Alpha streptococcus,except pneumococcus Enterococcus Oral anaerobes-peptostreptococcus,etc.Treponema pallidum and other spirochetes ActinomycesPenicillin-Mech
2、anism of Action Penicillin is a beta-lactam antibiotic Binds to penicillin binding proteins on bacterial cell surface Inhibits cell wall synthesisPenicillin and Pneumococcus About 30%resistant,15%intermediately sensitive Altered PBPs makes penicillin and sometimes cephalosporins ineffective Plasmid
3、mediated,possibly transferred from other species Plasmid also caries resistance genes to other antibiotics:macrolides,tetracyclines,sulfa drugsPenicillin-Neisseria Increasing resistance due to beta-lactamase production in N.gonnorrhea and N.meningitidis Unless organism proven sensitive,do not use pe
4、nicillin empirically for meningitis or sexually transmitted disease.Penicillin-Dosing Mild infections-cellulitis,pharyngitis,etc.,lPenicillin V 500mg PO QIDlPenicillin G 1-2 million units IV Q4hrs Serious infections-meningitis,endocarditislPenicillin G 4 million units IV Q4hrs.Syphillisllatent:2.4 m
5、illion units benzathine penicillin IM Q week x 3 weekslneurosyphillis:4 million units IV Q4hrs x 10 days Adjust dose for renal failurePenicillin-Clinical Uses Syphillis S.pyogenes pharyngitis Actinomyces infections Subacute bacterial endocarditis due to pcn-sensitive alpha-streptococci Pencillin-sen
6、sitive pneumococcal and meningococcal meningitisAmpicillin-Spectrum Same gram positives as penicillin Enteric gram negatives(if sensitive):lE.colilProteuslSalmonellalShigella Respiratory tract gram negativeslHaemophillus influenzae,Moraxella morganii Pasteurella moltocida Listeria monocytogenesAmpic
7、illin and Enteroccocus Weak affinity for penicillin-binding proteins bacterostatic Must add aminoglycoside(gentamicin)to create bacterocidal regimen E.faecalis usually sensitive E.faecium usually resistantAmpicillin and Haemophillus About 40%of H.influenzae is resistantlProduces beta-lactamase Resis
8、tance overcome by use of beta-lactamase inhibitorAmpicillin and Salmonella Increasing resistance in salmonella makes it unreliable against typhoid fever.lAbout 40%resistanceAmpicillin-Dosing Mild infections-cystitis,pharyngitislAmoxacillin 500 mg PO TID Moderate infections-pyelonephritis,cellulitis,
9、osteomyelitislAmpicillin 1-2 gm IV Q6hrs Severe infections-meningitis,endocarditislAmpicillin 2 gm IV Q4hrs Adjust dose for renal failureAmpicillin-Clinical Uses Amoxacillin for ampicillin-sensitive UTIs In combo with gentamicin for enterococcal endocarditis Listeria monocytogenes infectionslmeningi
10、tislbacteremia Cat bite cellulitis+clindamycin Penicillin-sensitive alpha-streptococcal SBES.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 inducibleMechanisms of ResistanceR
11、ibosomalmethylationReducedpermeabilityCH3EffluxEnzymaticinactivation=drugAlteredbindingsitesNucleusDNA gyraseBeta-lactamase-Resistant Penicillins Methicillinlhigh risk of interstitial nephritis,no longer on market Nafcillin Oxacillin Dicloxacillin(PO)Nafcillin/Oxacillin-Spectrum Oxacillin-sensitive
12、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 ofNafcillin/Oxacillin-Pearls Most potent anti-staph drug made Excellent CNS penetration(staph
13、 meningitis)No dose adjustment for renal failurelpredominantly hepatic excretion Watch out for:lleukopenialthrombocytopenialinterstitial nephritisNafcillin/Oxacillin-Clinical Uses All MSSA infections:lEndocarditislMeningitislOsteomyelitislPneumonialAbscesseslCellulitisAnti-pseudomonal Penicillins Ca
14、rbenicillinlno longer on the market Ticarcillinlonly on market as Timentin Piperacillinlhard to get as piperacillin alone,usually only available as ZosynPiperacillin-Spectrum Pseudomonas Enterobacteriacae group Beta-lactamase negative Moraxella,Neisseria,Haemophillus Same gram positive spectrum as p
15、enicillin Same anaerobic spectrum as penicillinPiperacillin dosing Mild to moderate gram negative(non-pseudomonal)or streptococcal infectionsl3 gm IV Q6 hrs.Moderate to severe pseudomonal infectionsl3 gm IV Q4 hrs.lOr Piperacillin/tazobactam 3.375 gm IV Q4 hrsBeta-lactam/Beta-lactamase Inhibitor Com
16、binations Unasynlampicillin/sulbactam Timentinlticarcillin/clavulenate Zosynlpiperacillin/tazobactamUnasyn-Spectrum Streptococci MSSA All anaerobes Beta-lactamase-producing gram negatives Enterococcus-bacterostatic Penicillin-sensitive pneumococcusUnasyn-Dosing Mild infectionsl1.5 gm IV Q6 hrs.Moder
17、ate to severe infectionsl3.0 gm IV Q6 hrs.Adjust dose for renal failureUnasyn-Clinical Uses Head and neck infectionslPeritonsilar abscesslSinusitislMastoiditislMandibular osteomyelitislActinomyocosis Infected Bite WoundslHumanlDoglCat Diabetic Foot infections,including osteomyelitis Culture negative
18、 endocarditisZosyn-Spectrum Streptococci MSSA All anaerobes Beta-lactamase-producing gram negatives Enterococcus-bacterostatic Piperacillin-sensitive pseudomonasl18 gm per 24 hrs Zosyn-Dosing Usual dosingl3.375 gm IV Q6 hrs.Fulminant sepsisl4.5 gm IV Q6 hrs.Pseudomonas sepsisl3.375 gm IV Q4 hrs Adju
19、st dose for renal failureZosyn-Clinical Uses Intra-abdominal infections Nosocomial aspiration pneumonia Diabetic foot infections when Pseudomonas might be involved Pulmonary infections in patients with bronchiectasis or cystic fibrosisCephalosporins Inhibit cell wall synthesis-peptidoglycan Side eff
20、ects are mildlrashleosinophilialleukopenialleukocytosislbiliary sludge(ceftriaxone)lthromobocytosisFirst Generation Cephalosporins Cefazolin-Ancef IV Cephalothin-Keflin IV Cephalexin-Keflex PO Cephradine-Velosef PO Cefadroxil-Duricef POAncef-Spectrum Staphylococcus Streptococcus E.coli,Proteus,Klebs
21、iella if sensitiveAncef-Clinical Uses Any MSSA infectionlCellulitis(2 gm IV Q8 hrs.)lOsteomyelitislEndocarditislPneumonialNot for meningitis Any Lancfield or viridans group streptococcal infectionslEndocarditislCellulitis Sensitive enteric gram negative infectionslUTISecond Generation Cephalosporins
22、 Cefuroxime IV-Zinacef Cefotetan IV-Cefotan Cefoxitin IV-Mefoxin Cefuroxime axitil PO-Ceftin Cefaclor PO-Ceclor Cefprozil PO-CefzilCefuroxime/Cefotetan-Spectrum H.influenzae Anaerobes Staphylococcus Streptococcus Enterobacteriaceae1st vs 2nd Generation 1ST GENERATION H.influenzae-S.aureus+Streptococ
23、cus+Moraxella-Gram negatives+Anaerobes-2ND GENERATION H.influenzae+S.aureus+Streptococcus+Moraxella+Gram negatives+Anaerobes+Cefuroxime-Clinical Uses Upper respiratory tract infectionslsinusitislperitonsilar abscesslotitis medialetc.,Lower respiratory tract infectionslpneumonialacute bacterial bronc
24、hitis Urinary tract infectionCefotetan/Cefoxitin-Clinical Uses Intra-abdominal infectionsldiverticulitislintra-abdominal abscesslperitonitislcholycystitisletc.,Osteomyelitis Diabetic foot infectionsThird Generation Cephalosporins Cefotaxime IV-Claforan Ceftriaxone IV-Rocephin Ceftazidime IV-Fortaz C
25、efixime PO-Suprax Cefpodoxime PO-VantinClaforan/Rocephin-Spectrum StreptococcilViridans,Lancfield groups,pneumococcus S.aureus Enteric gram negatives H.influenzae Neisseria meningitidis and gonnorrhea some anaerobesFortaz-Spectrum All gram negatives,including Pseudomonas Weak if any gram positive co
26、verage No anaerobic coverageClaforan/Rocephin-Clinical Uses Meningitis-2gm Q4 hrs/2gm Q12 hrs Community-acquired pneumonia UTI Upper Respiratory Tract Infectionslsinusitislperitonsilar abscess Intra-abdominal infectionsFortaz-Clinical Uses Hospital-acquired pneumonia Hospital-acquired UTI Post-op me
27、ningitis Intra-abdominal infections Pulmonary infections in patients with cystic fibrosis or bronchiectasis Nail-puncture cellulitis/osteomyelitisFourth Generation Cephalosporin Cefepime IV-Maxipime+NSHCI H2NNHNOOCH3HHONSCOOHNCH3 H2OcefepimeCI-ZWITTERIONIC CHEMICAL STRUCTURE*Bcher K et al.J Antimicr
28、ob 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*lElimination was almost entirely renal,with no evidence of accumulationlMinimal changes in intestinal flor
29、a(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 calcoa
30、ceticus 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 Pro
31、videncia 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 au
32、reus(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 streptococciMaxipime-Clinical
33、 Uses Hospital-acquired pneumonia Sepsis in prolonged hospitalization Intra-abdominal infectionsCephalosporins1st Gen2nd Gen3rd Gen4th GenGPC+GNR+Anaerob.+Carbipenems Imipenem-Primaxin Meropenem Merem Ertapenem Invanz Doripenem-Dorimax Inhibit cell wall synthesisPrimaxin/Merem/Dorimax-Antibacterial
34、Spectrum Covers everything but:lMRSAlStenotrophomonaslB.cepacialpcn-resistant enterococcus(only bacterostatic vs.pcn.sensitive strains)lC.difficilelsome pcn-resistant pneumococcusImipenem-Primaxin Toxicity Rash-50%cross-allergenicity with penicillin Seizureslrenal failure(high serum levels)lintracra
35、nial pathology(lowers seizure threshold)Nausea/vomiting Leukocytosis ThrombocytopeniaMerem-Toxicity Same as Primaxin,except Minimal seizure riskErtapenem spectrum All gram positives(except MRSA,and vanco-resistant Enterococcus faecium)All gram negatives(except pseudomonas)All anaerobesVancomycinVanc
36、omycin Class-glycopeptide Inhibits cell wall synthesis,and RNA synthesis(double action)Binds to d-ananyl-d-alanine portion of cell wall precursorVancomycin-Toxicity Red mans syndromelhistamine release during too rapid infusion Ototoxicitylcommonly irreversiblelassociated with sustained high doses(pe
37、aks 30)Nephrotoxicitylvery uncommon now ototoxicity and nephrotoxicity amplified in presence of aminoglycoside or high-ceiling diureticsVancomycin-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)T
38、arget trough 15 20 ug/dl(more severe infections or those with penetration issues)If trough high-lengthen interval If peak high or low-adjust doseVancomycin-Dosing051015202530350 hr3 hr9 hr15 hrVancoConc.Vancomycin-Dosing Random Levels Use only when patients serum creatinine is unstable Write order t
39、o 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 VancomycinTrimethoprim/Sulfamethoxazole Each component inhibits sequential steps of tetrahydrofolic acid synthesis thus act synergistically High or
40、al bioavailabliltyTrimethoprim/Sulfamethoxazole Toxicityl75%adverse reactions involve skin urticarial rash most common Stevens-Johnson Syndrome,exfoliative dermatitis,toxic epidermal necrolysis are rarelallergic cholestatic hepatitislreversible drop in creatinine clearance in patients with normal re
41、nal functionlirreversable renal failure in patients with renal diseaseUses of Trimethoprim/Sulfamethoxazole Useful alone or in combo with Rifampin in mild MRSA infectionslUTI,Bronchitis,cellulitis Switch to PO TMP/SMX after a course of IV vancomycin Use in combination with vancomycin and rifampin in
42、 serious MRSA infections Drug of choice for Stenotrophomonas maltophilia Drug of choice for PneumocystisRifampin 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,res
43、istance develops rapidlyRifampin-Toxicity Chemical hepatitis GI intolerance Increase serum creatinineRifampin-Drug-Drug Interactions Increases hepatic metabolism of many drugs thus reducing their serum levels:lcoumadinltheophylinelfluconazole,itraconazole,ketoconazoleldigoxinlcyclosporinlpropranolol
44、lsulfonylureaslprednisoneldilantinSynercid-quinupristinSynercid-dalfopristinSynercid Class:Streptogramin Quinupristin and dalfopristin act synergistically Mechanism of action:bind to 50s ribosome to inhibit protein synthesisSynercid-Antibacterial Spectrum MSSA-bacterocidal MRSA-bacterocidal Vancomyc
45、in-resistant E.faecium-bacterostaticlunreliable vs E.faecalis Coag.neg.staph Corynebacterium jeikeium S.agalactiae S.pneumoniae(including pcn-resistant strains)S.pyogenesSynercid-Administration IV form only 7.5 mg/kg IV Q8hrs No adjustment for renal failureSynercid-Drug interactions Inhibits cytochr
46、ome P450 3A4,thus increases levels of:lcyclosporinlBenzodiazepineslCa channel blockerslantihistamineslSteroidslStatins Synercid-Side effects Infusion site pain and inflammation Myalgias Arthralgias NauseaZyvox(linezolid)Zyvox-(linezolid)Class-oxazolidinone Acts on 50S ribosome 100%oral bioavailabili
47、ty Bacterostatic 65%non-renal excretion-no dosing adjustment for renal failure Dose:600mg IV or PO Q12hrs Minimal drug-drug interactionsZyvox-Spectrum of Activity*=FDA indication Staphylococcus aureus(MSSA*and MRSA*)Enterococcus faecalis(including VRE)*Enterococcus faecium(including VRE)*Streptococc
48、us pneumoniae(pcn.-resistant and pcn.-sensitive*)Streptococcus pyogenes*Streptococcus agalactiae(gp B strep)*Coagulase negative staph(including MR-CNS)Viridans group strep Pasteurella multocidaZyvox-Toxicity Thrombocytopenia-about 10%Diarrhea-8.3%Headache-6.5%Nausea-6.2%Vomiting-3.7%Insomnia-2.5%Constipation-2.2%Rash-2.0%
