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by: Madelyn Rodriguez


Madelyn Rodriguez
GPA 3.8


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This 34 page Class Notes was uploaded by Madelyn Rodriguez on Wednesday September 9, 2015. The Class Notes belongs to MEDCH 401 at University of Washington taught by Staff in Fall. Since its upload, it has received 15 views. For similar materials see /class/192632/medch-401-university-of-washington in Medicinal Chemistry at University of Washington.

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Date Created: 09/09/15
ANTIMICROBIAL AGENTS INTRODUCTION A DEFINITIONS B IMPACT OF ANTIMICROBIALS ON HEALTH CARE C HISTORY D PRODUCTION ISOLATION PURIFICATION OF ANTIBIOTICS E THE RAPY GUIDELINES 1 Antibiotic must reach site of infection 2 Bacteriostatic drug may work if host defenses are adequate 3 Bacteriocidal drug may be needed in medically compromised patients or in severe infections F FUTURE II COMMON MECHANISMS OF ACTION OF ANTIMICROBIALS Cell wall synthesis DNA replication Beta Iactams Quinolones Vanoomycin Metronidazole Cycloserine Bacitracin Polymyxm DNA I RNA synthesis mRNA Rifampin Ribosomes 7 v V v0 Protein synthesis 50 ribosomes Antimetabolites Chloramphenicol Sulfonamides I Macrolides Dapsone Protein syntheSIS Clindamycin Trimethoprim 30 r39bosomes Linezolid AmlnoglyCOSIdes Quinupristim Tetracyclines dalfopristin Basic sites of antibiotic activity Adapted from Murray Rosenthal Pfaller Medical Microbiology 5th Edition ElsevierMosby 2005 A INHIBITORS OF BACTERIAL CELL WALL SYNTHESIS eg Penicillins Cephalosporins Vancomycin 1 Bacterial cell walls and membranes a Grampositive bacteria surface macromolecules peptidoglycan cytoplasmic membrane cytoplasm b Characteristics of Gm bacteria 1 less developed biosynthetic capability 2 high internal osmolality 3 relatively simple cell wall mner nemhrane a umnmniGmOhwx u hem mama mum clpmw hem milpuve lnwamnhhw wruka s Madam Lhnpepudn wmlwu pemuwmmuumm Emma pannclumhuldkxumipanai Purim Maw mm mm mumWm ammmm Ch 1 2 a A 5 2 amammxgmmkmmuangxwmw 0mm gm 2 gm phaspharenakpymvam 4 0 an H0013 Ma a 5 013mm 5 quotmm g umsmva Macaw mummu and NAM Biosynthe sis of Glycopeptide Precursor Formation in cytoplasm a UTP NAG phosphate PP UDPNAG PEP 2 UDPNAM Lala Dglu LIys Lala racemase UDPNAM tripeptide 1 Dala synthase lt 1 DaIaDala UDPNAM pentapeptide 1 inhibited by cycloserine 2 inhibited by fosfomycin NH 3 H NH 3 H O C C H C C H H 3C HC CH PO 3H 2 I I fosfomycin IC O H C O o 9 o 9 N H 2C C CO dala cycloserine PO 3H 2 phosphoenol pyruvate b Formation of Linear Peptidoglyoan on cytoplasm side of membrane surface UDPNAM pentapeptide J UMP Pphospholipid I carrier phospholipid P P NAM pentapeptlde UDPNAG N lt UDP phospholipidPPNAMNAG phospholipid PP L39ala Dglu llys Dala ala phospholipidPPNAMNAG D glytRNA i lala tRN Dglu llys Gly Dlala 3 cwopbsmm membmne I cytodasm gmwmg NAMNAG bound to peptidoglycan acceptor peptldoglycan lala Dglu llys Gly Dala Dlala 2 inhibited by vanoomyoin binds to daladala 3 inhibited by baoitraoin c Crosslinking ofthe Peptidoglycan glycopeptide polymer NAM NAG etC glycopeptide polymer NAM NAG etc L ala I ala D glu D glu IIys glyg yS gly5 D Iala gt D Iala D Iala D Iala transpeptidase D ala glycopeptide polymer NAMNAG glycopeptide polymer NAM NAG I ala I ala D glu D glu ys gy5 ys D ala D ala D ala 4 inhibited by penicillins and cephalosporins Pentaglycine Pep de B dge Chain 5 Penicillin binding proteins PBP39s of E Coli PBP of total PBP Function inhibition lethal 1 a 8 transpeptidases yes 1 b 2 07 maintenance of rod shape yes 3 2 septum formation i 4 4 5 6 5 Dalanine carboxypeptidase no 6 2 Figure 3 6 Stereomodels of pen icillin A and of the Dalanyl D al anine end of the peptidoglycan strand B The arrows indicate the CO N bond in the Blactam ring of penicillin and the CON bond in the Dalanyl D alanine at the end of the peptidoglycan strand From Strominger et al9 R CONH s Figure 3 7 Proposed mechanism i of transpeptidase inhibition by O N RCONH S penic1111n Penicillin occupies the OOH Dalanyl Dalanine substrate site Penicillin Enz N of transpeptidase the reactive fourmembered Blactam ring is broken by cleavage at the CON bond and the antibiotic becomes EnZ linked to the enzyme by a cova lent bond From Tipper and Strominger37 I Cl COOH TranSDeDtidaSB Penicilloyl enzyme 6 Autolysis Lysis of peptidoglycan occurs and accounts for bacteriocidal effect of Beta lactam antibiotics when synthesis of new wall is inhibited Lor 07 P 039 r O A T Growth OD540 o to 1 02 01 r Hours Figure 3 9 Effect of penicillin on the growth of a parent strain of Bacillus subtilis with normal autolytic enzyme activity and an autolysin de cient mutant Penicillin was added to cultures of B subtilis in the middle log phase of growth and growth was assayed by turbidity at 540 nm The arrow indicates the time of drug addition 0 parent strain 0 parent strain plus penicillin A autolysinde cient mutant A mutant plus peni cillin The parent strain was lysed whereas the growth of the mutant was halted without lysis The same phenomenon was observed upon the addition of cycloserine vancomycin or bacitra cin From Ayusawa et al63 Table 3 3 Susceptibility of 60 strains of Staph ylococcus aureus to oxacillin The minimum con centration of oxacillin required to inhibit growth MIC and the minimum concentration required to kill 999 of organisms MBC were deter mined for 60 randomly selected clinical isolates of S aureus The penicillin was bactericidal against 27 strains and only bacteriostatic against the other 33 It should be noted that the toler ant organisms will die very slowly if kept in the presence of a high concentration of oxacillin for many hours The data represent the mean MIC and MBC for each group with the range of values shown in parenthesis MIC MBC Isolates gml gml Sensitive group 030 22 01 16 02 125 Tolerant group 033 gt100 01 08 SO gt100 Source From Mayhall et al65 Table 1 a man mp m mum mq a7 mm M my mm m mm mp Pu rde mu m m m m m mm ram and MW ualpuadwp mmmugw mm u mmv q 7mm W mm t m M WWW r wwmww wwwmmm www w m W W W w u WWW i p N Vb N m V Wm m m Wr WWW h wwwmmu m mum mmquot mmmn rm mm mm m w W W WW n m mm W n W7 v rm NW MMLWMM Wm M w wmwwmm Wm waaamwww4 mmmWWWummmm m A N m Mm umWWW Mum Mp C n m mmlmwmw m M W wwwmwwwm 4 u v mmm w w i mm W H v Mm N wwwwuu 4 WW mu Wm M mu mm m mm W m V a r WNW q mm ume mm mm m m rm H mm W v M r m 39 mm mm m mm m Wm M m mm m awnmw ma mqmmmmm v WW Mum mg m m mp my mum mp r n Wm I quummqamxm wupulk u dummy m up mu m B INHIBITORS OF BACTERIAL PROTEIN SYNTHESIS 1 Bacterial Protein Synthesis a Ribosomes eukaryotes have nuclear membrane mitochondria or chloroplasts other organelles 1 80s ribosomes 2 subunits are 40s and 60s 3 are 50 larger than bacterial 4 bound to rough endoplasmic reticulum and are fewer in number Ribosomes prokaryotes bacterial 1 70s 2 80s and 50s subunits 3 not bound General Points 1 intricate process and many opportunities for inhibition 2 selective effect due to lack of 70s ribosomes in eukaryotes and different structural and functional proteins on the subunits 3 generally some effect on mammalian systems that may result in toxicity when higher doses are used B WEISS 5 O a 0 QQ mcrvmmrmnm mmmm mum a 0 0 a mmmm y m mm A mm am w pnxedhyhpdunk hmdna m m 5 mm mhlum m m mm mwmmm 1mm 9 ma mm rmlymmmmmw mqu Mupn xxlmmxll hemmuuudmdm m m s mbuml alhulemlnb m m m r mum in mm m s mmxm mhlum anumnhe mm Pamme m naml lV me mmauyhnmduxndumh um um mm mm m am m m mum m Abuspmx um um amykmenuryhxpmm ban nmemmadnn mumnxummum IquemealmRIlA mm 1 deuunxhxuemlymxem Wham m m mums mm mm bluemlymxem Mmemhyhmdmgm m m s mhlum munmknnmhmdmna m A m n nasmt w wemm 0mm mmvhd annmc Fem m anmolnuaznmpmzmvmmnuny m muoqu mm mama dummwnyun mmmmm 1m lnu hmmnnhluemi m quotmmquot mmbxlymxem mxhenshyhmdm mm mandalaIanmmummkhn mummmueiynxem mm by m1me mle annEMnm mnwmm m1 uan 1 mm H n max k ndtnxld ummlmtnmumn c Amlcmslu mmmnsopmcmm ymmu mmums 1 Amm vcaldzl hmdm K lnhammll mum am 1 mum e LII1me hmhw p12 pmuman K lnhammll mum dawn Lmdm WWW mm Lu W mhlumu xmlemm mm cm mm a n alum m dank mu anxdll E g E E a 5 g dawn mm m m mammm K lnhammd mm A ammuth wamm mumpxummmumsu hymn mum Erymww n Amman hmdlm sumumm damn mum s man humm nu muquot m Mmmplumnl m dubqu 0139 5mm mum 2 IL me mum a an umpepumum m mum erydrnrkun amman um lddmnnah ll w pepudz mum lavKW mummmmuvmmaau 12 INHIBITION OF NUCLEIC ACID SYNTHESIS AND FUNCTION 1 Rifampin binds to DNA dependent RNA polymerase 2 Fluoroquinolones blocks DNA gyrase topoisomerases H and IV S Antivirals discuss later ANTIMETABOLITES CIDH S ZNH R NH 2 NH R39 PABA sulfonamide Sulfonamides are PABA antimetabolites to inhibit folic acid biosynthesis AGENTS AFFECTING MEMBRANE PERMEABILITY peptide antibiotics eg polymyXin B amphotericin B antifungal and daptomycin III MECHANISMS OF TOXICITY A EXTENSION OF ANTIBIOTIC ACTION eg some inhibitors of bacterial protein synthesis effect mammalial protein synthesis HYPE RSENSITIVITY eg sulfa drugs penicillins TOXICITY UNRELATED TO ANTIBIOTIC MECHANISM eg hepatotoxicity due to trovafloxacin INDIRECT EFFECT due to perturbation of the normally protective microflora eg overgrowth ofcandida albicans eg overgrowth of other intestinal microbes to result in antibioticassociated diarrhea eg overgrowth of Clostridium difficile to result in antibioticassociated diarrhea anti bioticassociated colitis or pseudomembranous colitis 13 BATERIOCIDAL INHIBITORS OF PROTEIN SYNTHESIS I AMINOGLYCOSIDES all are UW formulary drugs O I H3C HSCHN m NH2 0 C1 R1 F CH3 NH 2 c1aR1 R2 H I D R2 C2 R1CH3R2H Gentamicin EJH NH R1 HZN 6 CH 2NH 2 CgH 2NH 2 m ID I NH 2 3 H2 0 4NH2 2 HO Ho 0 H2 m NHCOCHCH 2CH 2NH2 I39D 5 O 1 Tobramycin mi Amikacin H 204 HO NH2 HO NH2 i NH C NH2 4 CH NH 6 2 2 N HO NH cquot NH 2 Ho 0 HQ HZN NH2 3 0 CH3 NHZ ID Streptomycin Kanam Cin CHO Y HZOH O H ZOI ID NH 2 H 3c HN 1 History and Structural Characteristics Streptomycin was first isolated by Selman Waksman from Streptomyces griseus in 1943 and this was a breakthrough drug for TB treatment at that time Waksman received the Nobel prize for this Kanamycin was isolated in 1957 and was the drug of choice until Gentamicin in 1963 Tobramycin and Netilmicin were developed later as alternatives to gent Amikacin a semisynthetic analog is the most recent and is used when resistance to the others is encountered All aminoglycosides contain 2 or more sugars linked to an aminocyclitol ring They are very water soluble and not orally absorbed and are cationic at physiological pH In streptomycin the aminocyclitol ring is streptidine whereas in the others it is 2 deoxystreptamine Gentamicin is not obtained from Streptomyces sp but rather from Micromonospora purpurea Hence it is not spelled Gentamycin Amikacin is obtained by chemical modification of Kanamycin 49 2 MOA AG39s bind irreversibly to the SOS ribosomal subunit to decrease initiation and thus inhibit protein synthesis Unlike other bacterial protein synthesis inhibitors AG39s are bacteriocidal for reasons that are not well understood but in part is due to a misread of protein synthesis 3 Spectrum AG39s have a broad spectrum against Gram aerobes Gram activity is limited and usually depends on combination therapy with a cell wall inhibitor to weaken wall Gram spectrum may include Staph aureus including MRSA and Staph epidermidis Gram includes aerobic and facultative pathogens Anaerobes are not generally covered The AG s diffuse through porin channels in the outer membrane but need active transport to cross the inner membrane The transport does not occur in anaerobes A big feature of the AG39s is that they are synergistic with beta lactams Thus the combination results in a powerful antimicrobial effect The cation pump to cross the inner cell membrane can be a site of resistance to AG s 4 Use a Serious Gram negative infections due to Enterobacteriaceae including Enterobacter Klebsiella Proteus Providencia Morganella Serratia and Pseudomonas aeruginosa Use is being replaced by the less toxic cephalosporins and fluoroquinolones Two drug regimens beta lactam AG for serious infections are still useful b Enterococcus faecalis and E faecium combined with Vancomycin or possibly Pen G or ampicillin alone have 40 60 resistant c Very serious Staphlococcal infections eg MRSA as an alternate to other antibiotics combined with vanco MRSA may be sensitive 5 Resistance Since the AG39s are being used in serious life threatening infections resistance could result the death of the patient Thus it is critical that resistance patterns be determined and monitored There are 3 main mechanisms of resistance to the AG39s a Resistance due to production of plasmid mediated AG modifying enzymes This is the most common mechanism and acetylation adenylation and phosphorylation enzymatic modifications of AG39s are well described The presence of the substituent amide at position 1 with Amikacin confers resistance to enzymatic derivatization at all positions except position 639 If a pathogen is resistant to amikacin it is resistant to all other AG39s Amikacin should only be used for resistant pathogens b Resistance due to impaired transport into cell via cation pump in inner membrane Gm and anaerobes have this resistance Also Pseudomonas aeruginosa c Resistance due to altered ribosomal binding site 6 Disposition Metabolism Excretion 50 AG39s are polar bases that have poor oral bioavailability and do not penetrate cell membranes well They are excreted largely unchanged by glomerular filtration These agents do not cross the blood brain barrier even when the meninges are inflamed Because of the high potential for adverse effects blood levels should be monitored with the goal to keep levels as low as possible and still achieve a therapeutic level lmmunoassays on serum samples are routinely performed at most hospitals The Pharmacy Department is usually responsible to calculate the dose These calculations are often based on lean body weight and serum creatinine These procedures will be covered in other courses Beta lactam drugs inactivate AG39s when mixed together Administer separately Post antibiotic effect concentration dependent killing which argues for less frequent dosing with higher doses Doug Black will cover this in more detail 7 Adverse Reactions See quotboxed warning below from Facts and Comparisons Other less common effects are neuromuscular blockade due to too rapid IV infusion hypomagnesemia in some patients on restricted diets and contact dermatitis with topical use especially neomycin Generally keep protocols short lt 5d WARNING Toxicity Aminoglycosides are associated with significant nephrotoxicity or ototoxicity These agents are excreted primarily by glomerular filtration39 thus the serum half life will be prolonged and significant accumulation will occur in patients with impaired renal function Toxicity may develop even with conventional doses particularly in patients with prerenal azotemia or impaired renal function Ototoxicity less common but more serious Neurotoxicity manifested as both auditory cochlear and vestibular ototoxicity can occur with any of these agents Auditory changes are irreversible usually bilateral and may be partial or total Risk of hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations and continues to progress after drug withdrawal The risk is greater in patients with renal impairment and with preexisting hearing loss High frequency deafness usually occurs first and can be detected by audiometric testing When feasible obtain serial audiograms There may be no clinical symptoms to warn of developing cochlear damage Tinnitus or vertigo may occur and are evidence of vestibular injury Other manifestations of neurotoxicity may include numbness skin tingling muscle twitching and convulsions Total or partial irreversible bilateral deafness may occur after drug discontinuation Aminoglycoside induced ototoxicity is usually irreversible Vestibular toxicity is more predominant with gentamicin and streptomycin39 auditory toxicity is more common with kanamycin and amikacin Tobramycin affects both functions equally Relative ototoxicity is Streptomycin Kanamycin gt Amikacin Gentamicin Tobramycin Kanamycin amikacin and streptomycin appear in this relative comparison based on high dose kanamycin amikacin and antituberculosis streptomycin therapy Renal toxicity 5 10 of treated This may be characterized by decreased creatinine clearance cells or casts in the urine decreased urine specific gravity oliguria proteinuria or evidence of nitrogen retention increasing BUN nonprotein nitrogen NPNor serum creatinine Renal damage is usually reversible The relative nephrotoxicity of these agents is estimated to be Kanamycin Amikacin Gentamicin gt Tobramycingt Streptomycin Monitoring Closely observe all patients treated with aminoglycosides Monitoring renal and eighth cranial nerve function at onset of therapy is essential for patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction Evidence of renal impairment or ototoxicity requires drug discontinuation or appropriate dosage adjustments When feasible monitor drug serum concentrations Avoid concomitant use with other ototoxic neurotoxic or nephrotoxic drugs Other factors which may increase risk of toxicity are dehydration and advanced age 51 8 Products a b Parenteral drugs Tobraniycin is more potent against Pseudomonas then gent Amikacin should be reserved for infection resistant to gent and tobra Kanamycin is usually used for topical therapy of gut infections Usually try to keep peak serum levels of gentaniicin at 4 8 nicgnil Amikacin peak should be 16 32 but not gt35 Streptomycin is used for TB Oral agents Note this is for quottopicalquot GI effects only Kanamycin neon1ycin and paronioniycin The latter is used for intestinal amoebiasis 52 nmnonmwms x 0mm mamas 4man mm mm x dam um ma quotengama Sann mmhzw cmmm gums 7 mm dug H36 Th5 agents We 35m mm swipes mm mm so an mmomum for U1 causd hygzmmgam banana WWW o m mg g agents We muchhe phazmscuhndw maqu an m e em SPeclxumufedM ysgamst auohm yamrnegauvuntadmns an m mva mm seams New sge Shaves me e genua lvh tidal e m a swan mm mm gym Upuxsumuase n ms nu mesumnase n n supexcu s mm mm and um mks m we mama pm and m a mmmwmm mum n heycangu mm he Ce ExampeNm r h mm 5mm apmhkm especiallvumh mum gumnheae Pseudmonas and S sph Due 9 and mm gyms e M50 mum mm mmx 5mm emuxpumps 9 mm drug M50 change mpunnchannel m can lead 9 xsxs anne Q d Spectrum 1 broad Gram negative activity against most aerobes even some Pseudomonas strains Excellent against Enterobacteriaceae 2 Gram positive organisms vary in sensitivity The newer agents have good Gram activity including Strep as well as PRSP but not MR SA 3 Anaerobes only moxifloxacin 4 Syphilis not very effective 5 Other Chlamydia Mycobacterium tuberculosis MAC and certain other Mycobacteria are sensitive and these fluoroquinolones may be very useful 6 Mycoplasma new er drugs 7 Enterococcus no Pharmacokinetics T 12 4 12h and therefore BID or even qd dosing is possible39 they have excellent tissue penetration and some penetration into CNS but not usually indicated for CNS infections Excellent for intracellular infections like Chlamydia MAC and TB Mainly eliminated via kidney39 some in bile39 Cipro and newer agents have excellent bioavailability Uses 1 UTI especially for complicated infections involving Klebsiella Providencia Pseudomonas Proteus Excellent agents for UTI as they cover most potential pathogens including some Pseudomonas UTI 2 gut infections good eg Salmonella Shigella E coli and normal anaerobic flora is not extensively perturbed39 are excreted in the bile and reach high gut concentrations Are preferred drugs for traveler39s diarrhea 3 respiratory infections in cystic fibrosis often Pseudomonas Newer agents have indications for community acquired pneumonia Strep pneumo H flu M cat including penicillin resistant Streptococcus pneumoniae and anaerobic bacteria 4 osteomyetitis with Gram negative bacteria good bone penetration 5 Prostatitis 6 complicated and mixed infections due to aerobic gram negative bacteria resistant to beta lactams 7 Can also be used for acute exacerbations of chronic bronchitis H flu Moraxella catarrhalis E E7 pneumonias including community acquired pneumonia using the new agents 8 STD cover N gonorrhea but resistance is increasing and many have a STAT dose indication for uncomplicated gonorrhea A 7 day regimen is needed for Chlamydia however so Azithromycin STAT is preferred A fluoroquinolone plus Azithro given STAT will cover both gonorrhea and chlamydia Not effective for syphilis 9 Skin and skin structure may work39 have some activity against staph usually not MR SA and strep especially the newer agents 10 bioterrorism Bacillus antracis Adverse Effects 1 good safety profile with most but there have been problems 54 Table quot h Fluoroquinolones have been approved for marketing by the FDA based on good safety profiles in the clinical trials only to discover serious adverse effects when in actual use in larger populations eg temoflaxacin withdrawn in 1992 six months after introduction due to renal toxicity hemolysis and hepatic toxicity seen in 15000 patients eg trovafloxacin approved in 1997 with great promise due to impressive potency and spectrum Now withdrawn due to hepatotoxicity eg grepafloxacin and moxifloxacin prolonged QT interval effects causes worry Grepafloxacin has been removed from the US market All fluoroquinolines can do this Clinical significance 2 GI problems 5 3 CNS lt 1 headache seizures dizziness confusion but not to be given to patients at risk for seizures 4 children not recommended for those lt 18 years old due to risk of bonejointcartilage erosion problems seen in animal studies unless benefit outweighs the risk eg cystic fibrosis complicated pyelonephritis 5 adult cartilage weakening 6 pregnancy lactation no see 4 7 phototoxicity especially those with a fluorine in position 8 eg sparfloxacin39 this is now off the market Drug Interactions Ciprofloxacin is a CYP1A2 inhibitor and has been reported to increase blood levels of theophylline and caffeine Newer agents are weaker inhibitors Polyvalent cations form chelates that have reduced absorption eg antacids multivitaminmineral combinations iron products calcium products dairy products Allow a 4 6h interval Summary excellent well tolerated but expensive oral drugs for serious infections less expensive than IV drugs much more expensive than narrow spectrum oral agents Agents available now and F l 39 Generation I Name I Use Comment Structure 55 First cinoxacin UTI rarely used 0 Cinobac 0 0 C I I OH O N N N CHZCH3 quinolones nalidiXic acid UTI rarely used 0 Neg Gra1n O Ijl H3C N N CHZCH3 Second ciprofloxacin general best Gm O Cipro now generic F COOH HN N N U A levo oxacin general some Gm O Levaquin coverage F COZH N N H CN O CH3 3 H lomefloxacin general photosensitivity O Maxaquin 8 F F COOH N N HN d2Hs CH3 ofloxacin general 0 Floxin F COOH I CH3N N N 0 CH3 nor oxacin UTI was the first FQ O Noroxin F COOH HN N N I C2H5 56 Third gatifloxacin Now only CH Tequin an 3 O O ophthalmic F OH product HSC I I HNQ OCHgA moxifloxacin general 0 O Avelox F OH H H N H gemifloxacin general Factive CH3O N HZN j UW Formulary Agents Ciprofloxacin Cipro Bayer and now generic oral and IV Excellent Gm activity but limited Gm activity Indicati OHS Acute sinusitis LRI Nosocomial pneumoniae IV Skin or skin structure Bonejoint UTI Uncomplicated cystitis Chronic bacterial prostatitis Infectious diarrhea Gonorrhea 500 mg stat AND inhalation anthraX Levo oxacin resistance is on the increase Levaquin Ortho McNeil oral and IV l isomer of o oxacin more potent compared to ofloxacin Gram activity as well as reasonable Gram numerous approved indications acute sinusitis acute exacerbation of chronic bronchitis nosocomial pneumonia community acquired pneumonia complicated and uncomplicated skin and skin structure complicated and uncomplicated UTI 57 k acu te pyelon ephitis pro statitis UTI available as 250 mg 500 mg and 750 mg tablets and for IV use dose 500 750 mg q d X 10 14 Moxifloxacin Avelox Bayer approved Jan 3900 broad spectrum agent but best Gm coverage of all binds to topo II and topo IV no p450 effects but small prolonged QT interval has been reported q d dosing indications for acute sinusitis chronic bronchitis CAP uncomplicated skins skin structure infections some antianaerobe activity has better Gm activity than levofloxacin but diminished Gm activity Some evidence that development of resistance may be slower than other fluoroquinolones It is not eliminated exclusively via the kidney so is not a good UTI drug Best used for respiratory infections due to Gm pathogens Patient counseling 1 avoid antacids Within 8h before and Within 2h after dosing Best to avoid dairy and multivitaminmultimineral and calcium products Within this Window also With qd dosing this is not a huge burden 2 inform if experiencing tendon pain 3 inform if experiencing severe or prolonged diarrhea 4 inform if have history of cardiac arrhythmia 5 be careful With caffeine if taking cipro 6 use sunscreen if taking lomefloxacin 7 usually not to be given to children lt18 58 CHLORAM PHENICOL NH D CHCl 2 OZN CIH CH CH 20H O I This potent broad spectrum antibiotic is reserved for use in serious infections where other less dangerous agents have not worked It penetrates into the CNS well and can be used for meningitis The danger relates to the risk of serious and fatal blood dyscrasias aplastic anemia thrombocytopenia granulocytopenia It occurs in 140000 courses of treatment The rare aplasic anemia which is irreversible is the most feared because close monitoring may not prevent A reversible bone marrow suppression due to inhibition of bone marrow cell mitochondrial protein synthesis is more common It is available and widely used OTC in some developing countries Must monitor blood picture frequently during therapy Infants don39t form the glucuronide metabolite efficiently and may develop the quotgrey baby syndromequot probably due to inhibition of mitochondrial respiration 59 Bacteriostatic Inhibitors of Protein Synthesis L TETRACYCLINES NCH3Z H hf CHsk Demeclocycline Minocycline NCH32 NCH32 HSC H O I H OH 39 H OH O He J a O 3 C V N dH H2 NH2 H30 CH3 H OH o OH o Tigecycline Doxycycline All are on UW formulary 1 Chemistry History Tetracyclines consist of 4 fused rings with substitutions on positions 5 6 and 7 They have different pharmacokinetic properties but the same spectra Tigecycline is new It is less prone to pathogen resistance They are sometimes grouped into short acting tetracycline intermediate acting demeclocycline and long acting doxycycline minocycline The first chlortetracycline was isolated in 1949 from Streptomyces aureus found in soil Doxycycline and Minocycline were introduced in the 196039s Tigecycline was approved in 2005 2 MOA Tetracyclines are taken up by bacteria by an active process They bind to the SOS ribosomal subunit and block binding of the aminoacyl t RNA to affect protein synthesis These drugs are bacteriostatic 3 Spectrum a General comment These are broad spectrum antibiotics with activity against Gram positive and Gram negative bacteria again st rickettsia Mycoplasma Chlamydia and some amoeba but resistance is widespread thus limiting the usefulness of the tetracyclines These drugs are still valuable for certain infections however Resistance has developed due to overuse especially in 60 developing countries and because ofuse in animal feeds Resistance is usually due to efflux or SOS ribosomal modifications Tetracycline resistance genes Tet are encoded on plasmids transposons and integrons and are therefore mobile The glycylcyclines are not subject to the activity of the present efflux pumps and bind tightly to the SOS ribosome even if modified Overuse of glycylcyclines will certainly result in resistance however The only commercially available g quot is to quot It is quot in more detail in a separate monograph b Grain positive If sensitive Strep and Staph can be treated but resistance is common Strep pneumoniae may be sensitive to doxycycline Community acquired MRSA may be sensitive also c Grain negative Many are now resistant d Other unusual pathogens are sensitive For example Rickettsia Rocky Mountain Spotted Fever typhus Chlamydia trachomatis Mycoplasma species Borellia burgdorferi Lyme disease Brucella Francisella Pasturella multocida Treponema pallidum and actinomyces Use a Doxycycline 100 mg BID or tetracycline 500 mg QID X 7d for Chlamydia trachomatis urithritis cervicitis conjunctivitis proctitis and lymphogranuloma venerium This is the number 1 STD in the USA Azithromycin is now preferred stat dose Neisseria gonorrhea resistance is too prevalent now in most parts of the country for effective use Therefore the recommendation is to use Ceftriaxone 250 mg 1M stat or Vantin po stat to cover the gonococcus b Lyme disease Borellia burgdorferi c Other miscellaneous pathogens Brucella Vibrio cholerae Mycoplasma pneumoniae walking pneumonia d Acne systemic and topical39 lower doses work well with fewer adverse effects eg 250 mgd e Doxycycline 100 mg q d to prevent Traveller39s diarrhea but ciprofloxacin is better 1 Malaria prophylaxis short term an approved indication for doxycycline is for malaria prophylaxis for trips lt 4 mos g Helicobacter pylori with Metronidazole and bismuth h anthrax Bacillus anthracis doxy 100mg q 12h for 3 months if exposed Disposition Excretion Absorption a Widely distributed including CSF 20 30 of plasma conc b Accumulates in growing bone and teeth Excreted in breast milk c Excreted in bile urine and feces d Note divalent cations Mg Ca Al Zn Bi will form a chelate which is poorly absorbed Definite interaction Avoid concurrent use with dairy products or antacids or iron products Doxycycline is okay with dairy products because it does not bind so well to calcium 61 e avoid taking with meals but doxycycline is okay with meals Adverse Effects a Permanent discoloration of the teeth if used during dentation period in children Not rec for children under 8 or during pregnancy b GI upset Common c Can cause hepatotoxicity and renal toxicity d Photosensitivity e Vertigo with minocycline e Don39t use outdated products T renal toxicity g Irritating when given IM or IV and can cause gastric distress h Superinfection due to broad spectrum and impact on normal intestinal and vaginal ora Candida overgrowth is common Products a Caps tabs suspension and powder for inj available generic products avail b There are some differences between the various tetracyclines For example minocycline has an indication for asymptomatic Neisseria meningitis carriers Doxycycline has an indication for anthrax including inhalation anthrax Minocycle has better Gram pos activity and maybe better for MRSA and PRSP Tigecycline Tygacil Wyeth a is the first marketed glycylcycline b poor oral bioavailability so IV use only c is much less susceptible to efflux pump resistant mechanisms and SOS ribosomal modifications d is approved for now for only complicated skin and skin structure infections eg MRSA and complicated intrabdominal infections eg Bacteriodes e the UW has it on the formulary in restricted for treatment of multidrug resistant infections Patient counseling a take on an empty stomach b avoid concurrent dairy antacids or iron39 wait 2h c use sunscreen d discard any left M M ACROLIDES Erythromycin Telithromycin Ketek Azithromycin 1 History and Chemistry The prototype drug is erythromycin Which was isolated in 1952 from a Phillipine soil microbe Streptomyces erythreus All the macrolides have a large macrocytic lactone ring attached to 2 sugars Clarithromycin is 6 methoxy erythromycin Azithromycin has an eXtra nitrogen in the lactone ring to give a 15 membered ring 2 MOA Bind to the 50s ribosomal subunit to block transpeptidationtranslocation reactions Similar to chloramphenicol and clindamycin Bacteriostatic but 39cidal in high doses 3 Spectrum These antibiotics are noted for excellent tissue penetration especially azithromycin and clarithromycin Erythromycin good activity against Gram positive bacteria and Gram negative cocci Also Mycoplasma and Chlamydia Clarithromycin is 2 4 times more potent than erythro and includes some pathogens not hit by erythro Azithromycin is somewhat less potent than erythro against staph and strep but has much better activity against many Gram negative pathogens including H influenzae Clarithro and Azithro have some antianaerobe activity Note no useful activities for Enterobacteriaceae in these bacteria the macrolides are weak bases and do not penetrate the outer cell membrane Under alkaline pH conditions uncharged they do have some activity Enterobacteriaceae also elaborate esterases which may hydrolyze macrolides 4 Uses a Upper and lower respiratory infections due to Strep Moraxella catarrhalis H influenzae For the Moraxella and H influ Clarithro and Azithro will be more potent Many Staph strains are resistant b Mycoplasma pneumonia quotwalking pneumonia c Legionaire39s disease Legionella sp d Chlamydia pneumoniae especially azithromycin e As alternative drug in penicillin allergic patient unable to take sulfas for infections due to Staph Strep H influenzae but fluoroquinolones may take over some of this use Erythro is inexpensive f otitis media the combination of Erythro and sulfisoxazole Pediazole is popular Azithromycin covers the common pathogens and is available as a suspension g Helicobacter pylori h STD Azithromycin Approved as a 1 g stat dose for Chlamydia trachomatis cervicitis and urethritis Compliance better than the 7d tetracycline protocol but cost may be a consideration Give in combination with an antigonoccal drug eg Ceftriaxone stat IM or cefixime stat po because the infection may have both pathogens present Azithromycin is not highly effective against N gonorrhea i Mycobacterium avium complex quotMACquot clarithromycin and azithromycin 5 Resistance Alteration of a single 50S ribosomal protein by methylation erm A B C genes results in resistance to the macrolides and clindamycin Decreased permeability also Also cleavage of the lactone by esterases from some Enterobacteriaceae Also efflux pump action The erm is inducible 6 Disposition Metabolism Excretion a Absorption erythromycin is unstable in stomach acid and the breakdown products are inactive The bioavailability is about 25 Ester derivatives or enteric coatings are used to protect the drug Clarithro and Azithro are more stable 50 bioavail and can be taken without regard to meals 64 b Distribution The macrolides have excellent tissue penetration but do not cross the blood brain barrier into the CNS well Azithromycin concentrates in cells with tissueblood ratios of 10 100 Tissue T12 of 2 4d c Metabolism Erythromycin is demethylated by cytochrome P450 3A4 to inactive metabolites It is a strong inhibitor of this enzyme as is telithromycin Clarithro is a somewhat weaker 3A4 inhibitor and azithro inhibition is minimal Erythromycin also weakly inhibits CYP1A2 Clarithro is metabolized to an active metabolite 14 OH d Elimination All are excreted in bile found in feces and urine Erythromycin is extensively metabolized N demethylation Azithro is slowly eliminated unmetabolized clarithro is metabolized to a 14 hydroxy active metabolite e Pharmacokinetic properties the macrolides are characterized by good tissue penetration and intercellular levels This is especially true for azithromycin Azithro is excellent for intracellular infections like Chlamydia 7 Drug Interactions Erythromycin and telithromycin and to a somewhat lesser extent clarithromycin have the potential to inhibit the metabolism of any other drug taken concurrently that is metabolized by CYP3A4 A few documented interactions with erythro include cyclosporin CYP3A4 carbamazepine CYP3A4 and digoxin Digoxin is a special case It is pumped out of cells by quotp glycoprotein which is inhibited by erythromycin This is a drug interaction not mediated by P450 Deaths due to cardio vascular toxicity have been reported with patients taking erythromycin and astemizole Hismanal or terfenadine Seldane These drugs are absolutely contraindicated with erythromycin They have now been removed from the market in the USA Clarithromycin is a weaker inhibitor but the potential still exists for significant drug interactions Dirithromycin and azithromycin seems to not be a problem but caution is advised Erythro and clarithro also inhibit CYP1A2 and can inhibit the metabolism of theophylline 8 Adverse Effects a Erythromycin is a very safe drug however about 20 of patients discontinue because of annoying GI effects Clarithro and Azithro are better tolerated b Diarrhea and GI irritation 13 32 with erythro 3 5 with clarihro 3 with azithro It has been shown that erythromycin results in high amplitude contractions from stomach to intestine are similar to that observed with motilin a GI polypeptide hormone It is a motilin agonist Erythro has actually been successfully used in cases of GI atrophy c Hepatotoxicity There have been deaths due to liver failure with telithromycin FDA now requires label warnings Elevated liver transaminases 1 2 with azithro Erythro has been associated with rare cholestatic hepatitis usually with the estolate salt in adults This is reversible d PMC the usual risk e Pregnancy Clarithromycin and dirithromycin have been associated with adverse effects on pregnancy in animals Do not use in pregnancy unless 65 there are no other reasonable options Use caution with azithromycin and erythromycin in pregnancy 1 Breastfeeding Erythromycin is okay for the others there is no information g myasthenia gravis Fatal respirator failure seen in some patients taking telithromycin This is a boxed warning now with telithromycin Products indicates UW formulary drug a Erythromycin base 250 mg 333 mg 500 mg tabs or caps also as enteric coated tabs or delayed release capsules The usual dose is 250 mg QID X 7 lOd b Erythromycin estolate tabs caps suspension39 use for pediatric patients only why use this form as it can be hepatotOXic c Erythromycin stearate tabs d Erythromycin ethylsuccinate tabs caps powder granules e Erythromycin lactobionate powder for injection 1 Clarithromycin BiaXin Abbott 250 mg and 500 mg film coated tabs Usual dose is 1 BID X 7d Metallic taste is bad Oral suspension available39 7020 tables 250 mg BiaXin XR 500 mg is now available It is now available generically g Azithromycin ZithromaX Pfizer 250 mg tablets Usual dose is 2 on day 1 then 1 qd X 4 Suspension for oral use is available as is a lg single dose packet ZithromaX is a top selling antibiotic It is now available generically h Dirithromycin Dynabac Muro H NH CH O CH CH O CH 3 2 2 EEIYCH3I etc this is a prodrug that is hydrolyzed upon absorption to erythromycylamine eliminated in bile and feces unchanged indications acute eXacerbations of chronic bronchitis H flu M cat or S pneumoniae secondary infections of acute bronchitis M cat or S pneumoniae community acquired 39 legionella pneumoniae S pneumoniae pharyngitis tonsillitis S pyogenes skin S aureus not MRS and S pyogenes take with food available as enteric coated 250 mg tablets Take one qd X 7 lOd worth the eXtra cost cost 6014 tablets i Telithromycin Ketek Aventis approved April 2004 66 long T12 9h 1 daily dose for 5 or 7 d binds to 2 sites on the 50S ribosomal subunit and does not induce erm PRSP is mutated at one site so that drug can still work indications like azithro except PRSP is included Not MRSA or erythromycin resistant Strep pyogenes indications bronchitis sinusitis CAP adverse vision prolonged QT interval muscle weakness hepatitis exacerbation of myasthenia gravis interactions is CYP 3A4 inhibitor pregnancy class 339 not recommended pediatrics not enough data39 not recommended place in therapy 10 Approved indications for formulary macrolides 8 b c Erythromycin URI mild to moderate LRI mild to moderate Respiratory tract Mycoplasma pneumoniae skin mild to moderate due to Strep pyogenes and Staph diphtheria amebiasis PID N gonorrheae in penicillin allergic Legionnaire39s disease Legionella pneumophilia Clarithromycin pharyngitistonsilitis acute maxillary sinusitis acute exacerbation of chronic bronchitis CAP skin MAC H pylori otitis media note pregnancy category C and safety in kids lt 6 months not established note clarithromycin is more potent than erythromycin Azithromycin COPD CAP STD for chlamydia pharyngitis tonsilitis skin MAC otitis media note azithromycin has less Gram and more Gram activity than clarithromycin 11 Patient counseling a b erythro do not take With food azithro avoid concurrent use of antacids small decrease in Cmax 67


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