[Elio seorion B sence Terany SUIESe Renal Func Poe ‘Adjustment for Renal alle: ‘reatnine Clearance (mL/min) rug oual Dose Taget >50 10-50 10 Adjustment for Disisis Rican 200 main Ne Ne Ne PIC: none _al2 hows PO & “Saguinavie 50 mph PO [NC (bo data) NC(o daa) NC Gro dats) H/C: none 0 dts) comin rere reversion, sul wi dys CL, cen eae (ei x mee SRD, estas eal ee: ‘esta ite ass he ee dose ts dali fl Soe forte amino HIN, ban mance’ vin nee: MD, maple ‘ds, tron macy sominiroons NC as change: OD, oc dy ain tztan: counsel ass (tse gen semely Utne orntled imo Same doer ar nto etme fps PO rs a rom Amol GR, Ber J, Bi ME. Dv rosin Ret als 4h Pildspi, American Cale of yas 198: psa, Aveda FT ‘Rosco Rea Ah ry fr Hi ps th ea sates! Anne Dee Sr Hen Rel 199921384 35; ed lili ses "Duta are used prio sas in ads Doser chilies hyo th nel pd ad fc sans of sem da ee aera sal ean ore ch ‘Senin ates wi ope ol unc, Doses fo menos ssl inden ey may ee om oe rome manatee get) “lin many sts at ot ved rch ene eb on el by weigh (wih nial Sno dg 50g) anh cleat (D8 He on) = CP) ‘eave craic cto: Tho res poston son guideline: nonureof sran dug conceals at be ued wie el cpl et td ecu of rp anintyest,sancomyn, Ontos Far rnd apy with septs sons inal chen, cen ion ea be {Sella dag se omtored Ney, Wh sparing ence ot sell omen an xpolion em he is area popes ‘Svan apes nthe snmmentan, When de das ms he pron othe vg, "neha oe hat th snd csc ace whe ‘Serum ee cncentas sha be mene. Chocaca sitio wih pn may 0 in swap enamine bramysn, Fert sbrin eee ‘Posten abaton gee got “pede etc so cree ie ESRD, The he thr a fr hep sn el uae ‘Tomcat wma tt tie ESRD, he eee te mr va el ii ‘Drs tren sal etc aetna techn bo mechan mpi ‘Newry etn xc cl SRD. “Orc ean osu wth rtnged igh doen ESRD. ‘Dimple he teed mer fhe eres cs fr ne a is Wh imp tl aon. ‘Dene ste esr se mele cams ESRD ‘Scum wh onenbor pk sonore ‘Sonm dn coment eth es pude ‘Serum recone shou onto nano sapaeson he cea in se nda ‘fp pce re ered leas pepeion card by be ney od crn gic rel ar dR bens knit Ihnen dine sald be ove cn ‘Reyso ipa ae merc and an ne Zo i ai ee so ek ‘Newey w ocaly cron ESRD, Emm 292 | Antimicrobial Agents John S. Bradley and Jason Sauberan Antimicrobial agents are essential in the therapy of bacterial infections. The approach to antimicrobial therapy is outlined in Chapter 289 (Principles of Anti-Infective Therapy), providing the clinician with an overview of the selection of agents based on the characteristics of infected children with respect to theie pathogens land antibioic susceptibilities, sites of infection, drug absorption, ‘isinbution and elimination, comorbidities, and a consideration of the benefits versus the risks of antimicrobial therapy. In this chapter, the agents themselves are discussed, providing a background on mechanism of action, spectrum of antibacterial activity, antibiotic resistance, and eurrent clinical use, A more detailed discussion for specific infections is found in each chapter describing that infection Table 289-1 provides more detiled information on the pharmaco- {week ‘nfs 5 ars Chien 2 hous Seeptomycie Pour abated 45%” Sime matic 10-30% a Renal Neonates, 10 hours nko it ‘le 2-3 hae Bascras Penilin G nue 15-30% 60-68% Peorats most sues, Hpac <305 Rona Neots, 1-3 nous Nose in aus and anode fi vases invert ih al ormultion poary ino cS {potato} niall. S12 hou Tesla om WR Pointe mow dues; Same at Same ‘Adls,05 hous oot ite CSE no ‘rnc pein ‘elt tet meningitis with dona tinction {vel ots ot Delosetin S70 i esti most sis, Hepatic TO Renal ‘Aut, 30-40 mintes Ghocmempsy es and ane i: “Oxsilin Hepae S08 Renal Neonates a infin, ‘able fet and aoe ii 2 hous poly ino CS Ads, 30-50 minates ‘ain atc Penetres mos tes, Hepatic ‘lay with Neonates, 2-55 hous ‘sorbed ia OL Tes and ano ‘erobepaic Infant 1-2 hour fret Not amine Fu port ino COE Feoteultion, Chien and ads, ‘ered oly eau 10308 30-9) mites ‘roeelia ss 20% Pentates most sis, Hepat me Renal Neonates 37 hour fers and amin Chile, 12 hare ‘is port ino CSF ‘dale, 1-15 hows Clawiaate ‘Wellameorbed 25% —Pensites mos tres, Hepatic extensive Renal ‘dls, 1 Boor tamoxciie es ad uae ld, 408 Pharmacokinetics poor io CSE called by slate) ‘Anplia 0 2B Peetmtes mon tes, Fn, Hepa 10K Renal Neowin = 1 wes, sein “tnd ammo tis poorly Selous monies io SP™ Neonates > 1 wer, abou hire, 1-2 hows ‘duty 105 tou [Notaiminiserad 36% Penecs mos ues, Hepatic HE ‘Renal ‘Adis I-15 hours rally ers and amie i poor int CSE Caen 30-0 50% Penettes mos snes, Hep minimal Renal Neonates, 3 ours {as ada saium) es and ame ‘Chiles 1 bor oor ni CSP “Tearilia Notadiniered 45% Penees ost aus, fee, Hepatic 10% ‘Real eats weck, TP how Conta[lisa seorion B. Anbnestveerpy Loe Soo Lo ora Protein Body Distibution and cent Biovatabity Binding _CSFPonetaton Metabolism Excretion tue (Eliinstion) Pipereilin Notadminigered 15-20% Penerates most seus, fetus, Hepatic minimal Rena ‘Neoats, 2-3 ous ‘nly ‘and ance Pid poorly ‘ary Infansfohilte, 03-1 hoor imo CE 20% ‘Adults 03 hour ices 10 1-13 bouts fo ih tose duet satin of hepatobiliary excretion (ose-dependnt i.) “Trobactm Not administered 20-23% Pnetaes most sous fous, Hepatic minimal Renal Tatas Lous (Gipeaclin Kinesis aly ‘and apalaie Mai: poly Childe, ae nat ino C8 4S minutes boor by tazobacam) etait Wellsbsorbed 20% Poses most sues, None Renal Slower Adal, 1-2 bors Tous and mai i sere ae sii eto CS than cephalexin) Cetizolin Pogerates most ssies,— None Renal Neonates 3-5 hows Tet, and smn ‘ale 15-25 bore sini nto CSP Cephalexin Wellatsoded 65% ——Penetrats most dines, es, Nowe Renal, ‘Neon, 3 bows ‘wih fod in aio i ome biary Inns, 25 hous ‘miialina CSE fae Golden acs howe ‘Cophedine Wellatsowed 10% Penetraes mos tissues; None Renal, ‘Ciena, 1 hour with fo ots, an amos i ‘ome bly minially into CSE (Cefacir Wellabsored 25% Peveates most tssues: Unknown Reo! Auli, 05-1 our kw ea: mpi, {oneal tnd CSF dsiuton elimination st tnknowa ste 2 in eval alu) u Cefoil on 36% enous mile-car fois Unknown Renal Intattiien nd tonsil, aden, monrenal 30% 15-2 hous Sian sot sss well: ‘Ads, 1-1 hous unknown fetal mnie nd CSF distbtion Cefarosine M7 asasetl): 50% Penouates mow dasves, Nae Renal eons 3-6 hous T0525 when Te, aa ste ad Infantile, 13-2 hows ven with fo nina ito CSF re ‘Adil, 12 Ros Coto ‘Netadminisired 755% Peneraer most tisues, _Hopatie minimal Renal Neonates, 1 hours ally fetus an smite fi Infant, snnimally int CSP 5 mous Loreto 08 but Penertes most sues, Nowe Reval ‘Ciena, ~ 1 owe ‘ith oo onsen eal, ao and CSF dsruton Cefinir 16.21% cap; 60-70% Penestesmosttsues; None Renal Adis, 1.7 bors 288 suspension known ea, ioe td CSF detiton ‘Cetinine 10-30% 65-70% Not wel studi Unknown Renu biliary Adu, hours ‘Celoerazone Notadminstxed 90% Pentates most tiswies, Hep < 205% ‘Biliary, Neonates, 6-10 hours enlly fet an! aici Oi ven ‘ores inversely ith ‘minal imo CSE 200% postnatal age) Iolosetiren 22230 ‘Adults 2 hours PART IV LabrataryDignesis ard Therap facts OiseeesAnnobol Agets CHAPTER 262 143800 rat Body Dstibuton and Agent Bioavalaity (SE Penetration Metabolism Excretion ‘4 (mination) Cefotaxine Notadminisiered 35-40% —Pentrates most issues, Hepatic Renal Neonates, 2-6 hours ally fens, and amnotc tad (varos aves) wih Mcguately into CSE estan and osnaalaz) Infarschilren, Tos hours Older citron, ‘5 minute Cofpsdoine 0 20-30% Penetates most issues, None eal ‘Adulte, 2-3 bows unknown fel, amniot, tnd CSF distbation Ceftartime NNotadminisred < 105% Penctrats most ues, None Rel Neca, 47 hours rally ets, and amniotic id Ivares invesey ih ‘Maguey ta CSF estatinal age) Als, 14-2 hours Ccfieten > 0% 65-77% Penaurtes most tissues; ‘Hepatic minimal Renal ‘Cruden, unknose fel nits 15-25 hour nd CSF asteoation| Cefizoxine Notadninisioed 31% Peetrats most issues, None Renal Neonates, 2-4 hours ally Tews, and amniotic a Adis, "2 ous mini into CSF Cefiacone Notadminitored 95% ——Penstats most issues, None Renal, ‘Neonates 919 hours only Tews, an amniotic tut Tiley Chiles, 47 hours Meguatyinto CSE" Adults, 6-9 hous Cetepime Notadminisered 20% Pentrates most tissues, Hepatic minimal Renal Neonates. 3-7 hours ‘only ets, and amniotic ts Childeenidts,~2 hous Mlesuateyinwo CSE" Or fLacras, onoRNcTAM treo (Notadministred 50-70% Pentats most sues, Minimal hydrolysis Renal Neonates <1 wee, ‘rly Tews, andampitic uid; atunknown te bliary minor hows ‘wail ato CSE (ares inversely wid ‘inte Noonate >I Week, 3 hos Childrens, 15-2 hours Cannes Meropenem NNotadministred Minimal Peosests most issues, Renal serum, Renal Neonates, 2-3 hours rally ets and arnicc Fit pte 20°25% —tliary minor Infants, 1.3 hou desu nto CSE" ‘ts, Uhr Tmigenem ) + Notauminiered 20%) Pencrates mon tse, fetvs Ren, erm, Renal iliary Neonates, 15-2. hour ‘lain (©) ‘val Soe (C) “tndanmiote fad, apie 20-298 “minor (elastin 58 hours) ‘Mgt nto CSF bot Infatschilden Felatelycontaniated Tos hours formeningtis, Adults = our Emapenem Notadminisered 95% Penctats inertial ids; Renal 20%, Renal biliary Infantshiren, rally Unknown fealamnioc, —bspaticminar minor 255 hours tna CSF dstbation Adolescent, ‘hours ‘Cuonowmnsacon sueanare (enon) PO forms (hao 80% Widely divtibved inating Hepatic Renal (as Highly variable; se text a palmate feta, amit, and CSF sucinate ste salt a lacuronihe salable ‘mebolie) alia nia Puuomogeotones asp QuroLonss Ciproftoaein GO-S0: > 90% 20-40% Penates most sues, fetus, Hepatle 20% Renal fees Neumann ‘nadolescents ‘moc id; minimally ‘hlden/adt swath CF into cSt 3-3 hous Continuedzz secrion ss ant-mecove inerapy harmacokinetcs, Ts oral Protein Body Distribution and ‘sent Biowalblty Binding CSF Penetration Metabolism Excretion tu (Eliination) “Gatifloxacin 6 20% Penetstes most uesoes ‘Minimal ena Infante, ‘cing CSF eta 27 hous nite unk Ad 8 hs Levotonssin oo BESS Penetmtes most sues, fetus, Minimal Renal Infante, rnin fi, CSF “7 hour Adult ot hous ‘Norflsacin 30408 101% Peneraies GU and Gl, fwws Hepatic Rema biliny Adal, 31 hous ‘and armite fui; CSF tensive Sinker z Naldveacid > 90% 90-95% Not widely dried; puis renal ‘Renal ®S5 a8 Adal 1S hours pena rena sb ‘iactne form) tral cones pace Telhromyein 51% 60-70% Widely disituted eta, Hepatic Renal, Diary Adults, 9-10 Bours ‘mote fad and CSF tk scones Clindamyein 0% 94% Penettes most tises fetus, Hepatic Biliary. seoal ‘Neonates, 36-87 hous ‘site id ial nor Gaver related 0 ino uainlmned CSF, but evotonal age and ‘aequaay into inPamed Dinh st orbran abacoss Infartehirenids, 28S hours Dapromyein Notadminstred ~90% Limite stitution: feu, Renal Renal Adults, 7-10 hors rally ‘anmotc, and CSP emt uw ‘aitanycin| 8 20-50% Widely dsribated incating Hepatic Bilary, renal, lanvehitren, feu amiode Mid ital > s0hou aia ito CSF Adults, 35-0 hous Canthromycin 50-55% ‘-0%% —Pengtates mont sss, fetus; Hepatic Renal 10-50% lane! (SF penton uknows (asdrug anda. 3-7 hous sctve netaboie) (dose-dependent) Enythrompein Poor 28-68% ROBO Pensa most es, fetus, Hepatic Biliary, remal Adult 1-2 hows teeetager ‘it Hid siialy isin (esol 3-8 hous) ‘sland font ites CSE Mersowmznes 10% < 20% Widoly distbutd ncading Hepa ‘Rema (60-80% Neonat, 225 to 109 Fetus mois id, CSF ‘th 10-20% hours aries inserely {sunchanged with gestational ag) rug biliary Chiles, tinoe (els nos Nimorassrow —Wallaborbed 90% | Mlnly urinary ent, prostate, Tswes Renal Bilary Adults and pce 20 mines Oxrounoones 10% SIG Penewates mest asus, Hepatic Real ‘Neonates, 15-10 ours Tinea Including CSF: Fes, ‘ware ier th ‘mnie Haid unkown festtonal 96) Infante, 2-3 hous ‘Aduls 3-6 hows Colistimcthte ——-POformnot_——-Miniml-_-Penetrates mos tues, Thawe minor and Real vide 2-3 hours \eton) aia otis and aa Mail: slow ‘dus, 15 hou sia pleural join. cates orb CSE ronens Rare 90.95% 60-90% Widely disuibuted including Hepatic Bilary, fase Tenis, amie Mus raul als, 2-4 hours ninimaly sto CS PART I Laboratory Dagoss and Terepy a rectus DiesesrtmerbielAcons CHAPTER 292 1425/0) Distrito Ora Protein Body Ditton ana Aaent Biooaiaity Binding CSF Penetration Metabolism Excretion ty (Elina) facile Poorly aborbed NA. Minimal systemic distribution Hope minimal Feces’ Minimal systemic veto poor oral ics ‘Shiortion sii, but igh ints Tumi concentrations Quine Poorly sorbed 55-785 Penettes mor tisues; Hepat, somersion Bilary, Adults 0.85 hours (Q) ‘sllepisin Notodministred (Q) minimally uo CSF; fetus, toscveral active renal = 15% 0.73 ure (D) ‘rally 126s amosoic Mai unknown metabolites 25-35 hous (+m) o “Thur (D+ a es = metabolites Siaronoumes 90 TRONETHOADAE Solfagiacine Too 20% Wily disuibuted,nelding. Hepatic wide Renal ice and Adal, 7-17 hous ‘ets, amniotic Mid, CSE individual ‘conju sation Terms) Sulfamethosaale 100% 65% Widely distibutd including Hepatic wide Renal (ee aad Ads, 912 hours Tus, amaote Nid, ‘nda ‘onjugted cr sation Terms) Sulsoxaole 100% 85% Widely distituedncuding Hepa wide ‘Renal (ree and Adalis, $8 hours ews, amaitc Mid, CSF inividal ‘emf Z sition forms) eee ‘Timethoprin 108 “186 Widely distributed including Hepat < 20% Renal Infanchilen, ‘ets, amniotic Mid, CSF 3.55 hors Advis $10 hours Dosyeyeline 0-100 82% Widely distributed incating Hepatic Rena biliary Aduls, -20 hous fetus, amiotc Mi: iimally into CSF Minocytine 0-0 To% Widely distitae including Hepatic Bilan. ‘Adal, 11-22 hous fetus, amniotic Md ‘iia ena minimally into CSF si Teurcyetine (Ty 75-805% 65% (7) Widaly distibuad including Hepate Kemal, bliary Adal, 7-10 hous (1) Demecloeycite(D) decreases 41-914 fei, smite ‘nim Adal, 10-17 ours (D) Signibeanly (Dy sii into CSF sith fod Tigecytine Limited. not 70-005 Widely dswibutad fetal, Hepaie 5-205 ‘liar, onal Adal, 40 hours dmiistered smite i ad i rly CSF unisown oa fist Nascomsein Nestle 30% Penerates most issues, fetus, None Rena biliary Neonates, 411 hours nsf oats ‘iio “saris nverey th frtewatialy ito CSE tonal as) Tafa 2 4 hors (Chiles, 2-28 fours (hc bros CSF ctor fn: aarieti Gi enon naan, 1, cy. “Agen wi uh mini tan so itary creo wil hve rng sms et wt el Ips, ‘Concent fg CSE seat next wa aed men Seeretences! dul 6 hous through the cell membrane to undergo further modification ultimately to create the peptidoglycan structure either ouside the cell membrane {in gram-positive organisms), of between the inner plasma membrane and outer membrane within the cell wall in gram-negative ‘oranisms). Linking ofthe disaccharide pentapeptide building blocks ‘occurs by transelycosylation, and creates repeating disuccharide Subunits (GIeNAc-MurNAc-pentapeptide) to produce long. glyean ‘chins.® Vancomycin and related glycopeptide antibiaties inhibit this Step in cell wall synthesis by binding tothe terminal bal, b-ala of the pentapeptide attached to MurNAc, and intesfering. sterically with the enzymatic function ofthe transgiycosylase.” ‘The mature glycan chains containing the repeating disaccharide units are subsequently liked by connecting the pentapptides located fon the MurNAc units from adjacent glyean chains. In this ‘ranspeptidation step, a stable bridge is created between glycan chains to form the two-dimensional peptidogiyean structure, The bett-lactam lass of antibiotics inhibits the transpeptidase function by binding covalently to the active serine site of the enzyme responsible for linking the two pentapeptide arms from MurNAc units on adcent lyean strands! The stricture of enzymes that are responsible for transglycosylation and transpeptdation varies somewhat between bacteria. Fortunately, the ative sites ofthese enzymes tend tobe quite[les section B se-etecve ey conserved. An organism often contains several transpeptidses, each fesponsible for a different cell wall function, including repair loneation, septation, and cell wall thickening, among others. Some Gf these enzymes appear to contain both transglycosylation and {tanspeptidation functions. Historically, these enzymes were identified by pentilin attachment to them, and are slso Known as peniilin- binding proteins, or PBPS. Beta-Lactam Antibiotics ‘The betwlactam antibiotics all share the capacity to inhibit the transpeptidase erost-linking of peptidoglycan in the final steps ff formation of the cell wall, Whereas the beta-lactam structure itself i consistent across all antibiotics in this class, the ring 10 ‘whieh the lactam moiety is fused variable, with relatively small Giflerences in the composition of the ring allowing for variable fctvity against the PEPs of both grant-positive and gram-negative bacteria (Figure 292-2), The addition of chemical “chains” © the ring. structures enhances activity against certain organisms, but Simultaneously may decrease activity against others, Differences in the charges of the antibiotic molecule affect the ability of the compound to reach and to bind to is target, particularly for gram negative pathogens Tn genera, the beta-lactam antbjotes are bactericidal with the ‘concentrations required for killin being very close to those required for inhibition of growth. The maximal bactericidal effect occurs on rapidly growing bacteria: in stationary phase, this class of antibiotics has substantially Tess impact on the viability of organism.” Resistance to Beta-Lactam Antibiotics Probably just as ancient as the natural antibiotics are natural mechanisms of resistance to them (Figure 292-3). Resistance to the beta-lactam antibiotics occurs primarily in four ways: (1) enzymatic hydrolysis of the beta-lactam ring by bacterial. beta-lactamase, rendering the antibiotic harmless; (2 alterations in the structure of the {tanspeptidase, so tha binding ofthe antibiotic tothe active serine site of the transpeptidase doesnot occur: 3) efflax pumps that, im gram- hneeative organisms, quickly and effcienly remove the antbioties from the periplasmic space before they ean bind tthe transpeptidase, ‘nd 4) alterations inthe gram-negative over membrane proteins that prevent the antibiotic from entering the periplasmic space. Each of these resistance mechanisms is variably effective and can lead either fo profound resistance or merely to slightly increased resistance that has no clinical impact. Unfortunately, some pathogens combine several resistance mechanisms, cach creating incremental increases in bets-lactam resistance, ultimately leading to the development of an ‘organism that is n0 longer susceptible o these antibiotics. “The chemical modifications of the beta-lactam ring structure that provide altered charges on the molecule can allow the new agent (e.g. Lmpisilin) to enter the gram-negative bacterial periplasmic space, in fotrast to an older agent (2. penicillin G) that could not. Side ‘chain cam also ereate enhanced stability ofthe antibiotic against one ‘or more of the hundreds of beta-lactamases shat have been identified. Unfortunately, new, more active and broader-spectrum beta- Jactamases are reported with disturbing regularity” Although many diferent efflux pump systems exist, changes in the siructure and ‘charge of the antibiotic ean decrease the affinity ofthe antibiti for the pump. while hopefully not dacreasing its affinity for the target transpeptidase (see Chapter 290, Mechanisms of Antibiotic Resistance) Penicillins ‘The penicillins ae the most commonly used antibiotics in pediatis, and ean be broadly divided into four different groups: (1) natural penicillins: ©) peniilinase-stable pencilins; @®) aminopenicillins and (4) extended-spectrum penicilins. ‘A. Abit Gass: Tanspoptidase ‘Natural pencins poncilins| tors Beto Lactam Anbbitce Peniilin G Petia V Benathine peniiin G Prcsine penclin G ‘Benethinerocaine penn ombitins| Peniiliogestable Methciin Oxseilin Nailin Coweilin Dicloaclin Aminopenicilins Ampciin ‘Amoxiilin Amoxillinflavlanate PART IV Latoraty Dlagoss ant Teapy of niectos Disases Spectrum of Acti? Gram-positive Swetceoci Groups A,B,C, G,F Niridns g1oup apococe Septocceuspevenonine Enerocoeet feccalie ‘Bnerocoeeus faeciun? Actinomyces Borin antracis Listeria mnoertgenes Gram-negative Enkenlis corrdens Detiserie mons Dalsea gonoriveae Paseurelo muociae Borrelia rgd ‘Spin mina Sieprobacius ‘monijormis ‘roponema pllaien Lepiospira speses naerobes Bacteroides and Prove spies (ron tet acme. prcing sis) utobacteri species Tedlneta species Clostridium species Ebecierum species Peptococeus spies Peplsrepococes pees Propionbacteriun spe Gram-positive Sueposocl(asabne or pencils) Stepilococeus enreus (Cexcopi MRSA ‘Gram-positive Sirptonee (as above foe pene) Enteroorcas fecal Eneneorcasfrcian® Usteria monocytogenes ‘Gramenegative Escherichia cai Haemophilus ofluncoe Neistera moningins Anaerobes For ampli: above for penis Aas sty ‘umoxciin Seapiglcoocus aureus except MRSA) eemopllasinenze, ea acamase producing tins Anaerobes [Xs above for pains, bt no aces: Bacteroides sod Prevorsle speciesAnticroblAgets cuaeren 292 1427/0008) 1c Wat at Agots Cl Walch Roots ‘A Antbiti Glas: Trnepeplsse nos ‘A Antboi ass: Tanspepitase ibis Bot-Lactm AntbiovesSpestum ot Acti Beta-Lactam bites Spectrum of Acti Twin cumase Cs speces Prod sin Ect species “Ampkilinfulbactam Ads activity to fpereocets pect ‘npcilin aie Stephslococees aureus Se eae ores excep MRSA) Ccamatosrons Escherihi col beta Fistgcosation Cephalon Gram-positive Tactamase pcg Cephariin Stptrsce sine Cefaotin ‘Gowps A, B.C, F Kiba species Cepatein Vins rip ‘Protas mia Cephatine epost Proteus gars (Cetadoxt Siepcccews Provide ranger ‘peunonise Provincia seat Stapiocncureueus Morgancle morgan ‘crept MSA AAnserobes Gram-negative ‘Av aone for penis, Eschrco colt ot ao nes 2 Proteus mri oS Saieeeg Gaese — oaeeatie evel species conta Soon iss sce ieee enon Ceforunide Varin group Extnda-peseum —Carbeniilin Gram-positive Cefaclor Strepoeee penciling “ewclin Sreptorocs ss above Cetin Saprceces Phen tor reins Cefn ipaewnonive Gram-negative Staplnfocccus aureus rena cot ‘except MRSA) Heenophtesnftuerace Gram-negative Protons mis ‘Bvheriehtacolt Proteus ralgeris Haemophilus iftuersae Morganela morgen (nto bet Pocalononae Incase ping ‘tengo airs) Provincia rege Kite species Brrrobcterpeies ‘Monatto eves ‘Anacrobes ‘Neisera gonorrhoeae ‘Bator: an Netseria mening Preval species Proteus miabils (son ets cans Providers roger pracing su) Salmoncle species usobacrertm species ‘Shige peies Veiner species AAnscrobo Clostridium species cries ad Euan species Pree specin Peprococon species (nonbeta latamare- Pepronptocncan producing sais ‘nec icept for setontin Sh toa lesser extent, “icrlinelnlnae Aids bi lvtanase ae Ppercilintaasbucam _producins wan of pmconiee Saphyfococns aureas Yello secies (Gxcep MRSA) Exbucterium peces Esherche cl Pee tas Haemophis inuencae ee tes ‘lca species ACES Serta mareions “Thin-genertion _Cefoaxime Gram-positive Giroacter spaces Ceftriaxone Septal ‘Bxeracter species Cefirine ‘Groups A. B.C.G,F Anseres Cefoperazone ein gr dceroies Cettoxime “reps revo species Conxine Swepiocoes (ictoing bet Cefpodoxime ‘preunoniae lastamasspecing Cettbien Scaphoococes crews sais) etinir (excep MRSA) usobctertam species Gramanegative Uinta species Girbacter scien Entersbater poses Continued[lies seorion B_ Anetve eeey | Coll Wall-Active Agents ‘Coll Wall-Active Agents: ‘Antibiotic Class: Transpeptiase inhibitors ‘A Antibiot hs: Tanepopiace nbs eta LovtamAntbitis Spectrum of Actiy? Bola: Lactam Antbitos Spectrum of Aci Heche cal ‘Gram-negative Hacmophinsnflencae Aatetobarte sees Cincning hes Girobacter sores Jactaate podocing ‘Brera pees stsinn Escherichia ca lesa species ‘icing EBL Morgenle morgan producing sais) Neltera sorthoese Garner vials Cinch bee eacmonhtas fuera incase producing ca soc Sins) tocading ESBL- essen mening producing sas) Prieur mirabilis Morgans organi Proteus gris Proves gar Provence rier Prolene ee Provident surat Preadomonascoraginoa Serta maresens excep erage) For eetidine and Serta pee ‘eloperizne: Anse Poewtomona were Bipdobacteram secs Aas Curie peer faceroles ad Eber sp Provan species Paprcoceur pecs (oon het terse Paprowrepocecces procing ain) tesen atobacrertun pets Propionibcterian ‘iacrerum spetes pedis Peptacoceus species ‘acteres 8 fot a Prete specie, Forever Celeime Gram-positive vrata et lcamase-produci Grog B.C. G.F aaa eee Fusobacterium species streptoeoce! = se spe Srepiencees Mowoucwe Asteoaam Gram-negative ae Croat species Staphylococcus ure Enurobecer pois (excep MRSA) Enehrcha cl Gram-negative ea ce eee ‘Reaver hin (including bet ‘seneratoncophal- tsar Sern icing pricing sais) Possdomonas ceraginsa) ithe species anaerobes, Protein Bacreres an Peendomonas Prevela specks deriincia Coombe lactamase Sera seis rodng era) et ‘Fusobacterium species 8. Antibiotic Class: Transglycosylase Inhibitors Vellonla species Eubacerum pecs Spectrum of Ac Pepococeus species ‘Guerre Vancomycin (Gra pose 5 Teichoplanin oot St Fifth-generation __Ceftobiprole iors fourth- eile. pi ag BOGE eplosprins, but ae oe sic inte MRSA sao aero ene a =e ee Eucrcoee eect ‘Camrneas———mipenem (with «Gram-positive re sist Sirepinncel Tacustse MEA, tx Meroperem Groups A,B, C.D, G.F fe venting Exupenemn idan rep iene ‘epost Sincomgeinesstint Spiococens Sains) rs Suponaceut e epidermidis Emersencene faecalis Slophylococeas aureus (except MRSA) Adnan species PART W Laboratery Diagnosis and Therapy of necbus Diseasesoe |.Cel all Active Agants 8, Aaiibioti las: Tansglyosylae Inhibitors 1 Coll Membrane Active Agents [A Auto Clas: Lipopeptides Dapronyein B. Antibiot Clase: Polymixine Coiistin |. Ribosome-Active Agents Macros ‘Aotinirobi Agents CHAPTER 202 1439) oe 1. Rosome-Active Agents 7. Rnb Cass Macroides actoboctins species ria manocynogenes ‘Nnaerabes Clovis cite “azstons ‘Aditya Spectrum of Activity ‘Stophylacocon enous (Gociding methielin resistin a vancomyei-esstnt site) Ererococeus faecalis ‘eancomyein-siscepible fan reset tans) Bnveroeoees feciun ‘ancomein-susceptible dan essa tans) Sueproeoce Groups A.B inns group streptoeoce Krroues Talhvomsin [Enterobacter aerogenes Excherichia col ‘iebsiela prcumoniae Pseudomonas aeruginosa ‘ctinobacter poses Cincbucter species Haemophatu species Salmenella species Shigella spose 1. Anibiote Cl ‘Macroupas Enytiromyein Gram-positive Corsnebacteriam ‘dplheriae Corynebacterium Listeria monocyrogenee Staphrlococau aureus Soeprococcus prewmonice Sohptocnecus pyogenes Gramenegative Boritella persis Legionella prewmophia Detsseria gonorboeae ‘Other pathogens Chlamdia echoes Entamoeba hitobytea Mycoplasma prenroiae Treponema pallian Termevcines ——‘Toracyline Minveyeline Doxyeyeline Ureaplasma wrealticum Claritromyein Gram-positive eneveines ——‘Tgecyelne ‘Staphylococcus aureus ‘Strepiococcus Sreptocacous pyogenes Gram-negative Hiaemoplls tnluenzae Moral catarralie Helicobacer pylori ‘Other pathogens -Mycoplesma pneumoniae CChiamsdophite presmoniae -Menbactetum ovine complex Gram-positive Staphyfococeus aureus ‘Strpeococet Groups A.B CEG. Viidus sroup steps Sirepioceces Bonet pertssis Gram-negative Hacrophits tflaencoe Heemophilas duerest Moravela catarrhalis [Neiwseria gonorrhoeae Other pathogens ‘Chlamdopilapneumaniae (Chlamydia trachomatis Legionella pneumophila Myeoplasma hominis yeoplama pacumoniae Ureaplasa trealtcum ‘Gram-positive Srphiococcas arent ‘Stopiococei Groups A, C ‘nd G Vins pou streplecoci Gram-negative Hcmophes inlacncae Monnetaeararrhatis Other pathogens Bordetella perms Mscoplasme pneumoniae Ligionella pnewnephia Ghlamydopia >pheunoniae B. Antibiotic Class: Tetracycines Gram-posive Acton species Gram-negative Vibrio cholerae Brucella spaces Canpylobacer species Franciela tularensis Listeria monocytogenes Yersinia pest Neier meningitis Neiseri gonorrhoeae Other pathogens Brea recurrent Chlanydopit psitact (Chana tachomats Mycoplatma proumaniae Ureaplasma Treponema pallid Eamoeba species Gram-positive Soplocoeci Groups A.B Virgins group streplocet Srepocoeeus ‘pneumoniae LEmerscocens forclis Entemscoceue faecium Continued[ER section Bart etre Taapy I Rlbosome-Retve Agents TABLE 292-2—Contiiied I ibasome- Active Agents ' nbiotie Class Tetracyaines Antboie Oas:Oxzzoicinon Siapiglocoecus auras Lsterla mance yogenes Clostridi perpen eprosrepococens species Gram negative Acinetobacter boul ‘enmonas Kydrphit Cierobacter fen Giroacer Kose: Enterobacter clooete Breroacter aerogenes Escherichia cot Klebsiella orton Klebili preumonie Pasourta mtocida ‘Sera marcescens Stenorophiomenas mato ‘Brcorldes species ‘Other pathogens Chlania choos Mycoplasma pesmoniae Ureapiasme Myeobeterion abscess ‘ycobaeteronchelonae Mycobueterion forniine 6. Antibiot Gas: Lncovamides Torconwares ———Clindamjein ‘Gram-postive Sueproocst Groups 8 Srepococes Deewneniae Staphsfocecas aureus Anaerobes Bucseroides frags Preveela usohacteriam species Peprosaces pees Peproseepocnecis ‘pies ‘Actbvomyces species Clos perfringens Propioibacteriam ot .Antibitc Gass: Aminoplyeosdes Soanooneomas —Sueptonyeln “Gramancgative Brocela species, Francs species Mycotctertin peeeee Gentanicin ram-postve Nedinicin Srophslacocens areas “Tobeamyein Gram-nezative ‘mika Eehedcha cl Klebiells species Buerobicter spies Sarai species ‘Cirabactr species ‘Morganetta morgan ‘Actietobcter species Providencta species Proteus mirada Proves agar Cees aero Paromomycin Enamoeke hstoltion Dientamoobo frags Coptosport species Orroesones Linezolid Anbiotie Cass Steptogramins “Simrrocasns— Quinypesany opin W.Mucleic Acid Active Antibatios| 1 Anite Clase ifamycin Risers itp Ritaain Rilpentne Biximin 8B. Antibiot Cass: Quinlones eunotons Naliixe acid Fixoroacsocows Chonan PART IV L2tortoy Dlagtose ane Tarany of Iectous Deeaes Geum positne Seepocoe Groups A. B irda group Suepocoss Srepecoecss Staphococes snes Enterocosfecun Enerococus favo Gram-positive Seaposoce Groups AB Suaphsincoe cous Entemcorrnsfecan Gram-positive Stphylococes aes Gramenegative Netter memati Hacmophies flucrsse other Mycobacterium “aberculois Mycobactrim atm comple: Mycobacterium ‘ubercuoals Mycabactrio alum complex Suscepble a conconztions achiev swith the asin! men: Campsabacier Escherichia cot Salmonella poses ‘Shigtt species Miro species Terai species ‘Gram-negative Escheicht cat ciate Morgaella morgane Proteus mivabie Protas vulgaris Provdenca eter ‘Gram-positive Sreptococens progres Srpococcaspreamoniae ‘Stophyococee aureus Enercon faecalis Dacia anthracis Gram-negative Aeranchar species ‘Reletobater species Escherichia coll Klebietia paeunonice Enterobacter cloacae Girobecer divers irobacer fen Campylobacter entProteus mire Proves vdgars Providenla reget Provincia star Sernaia marcescens Pseudomonas aeruginosa Merganella morsanl Sabmonet species ‘Shigella species Hacmophils inflensce Hemopiilas Moravella carats Netreria gonorrhoeae” Pasteurella multocida Vibrio spacies Yersinia nterocelioa Other pathogens Legionella prewnophi “Levoflonsin| Gattosacin, 6. Antbote Glass: tvolmadazoles ‘Metroniazole positive Swepreoesi ‘Group A Visdans aroup Smpinenceas Emermcocensfeccalls Staphylococcus aureus Actinomyces species acta ante Listeria monoclogenes Gram-negative Acintobacer species Escherichia coo Enterobacter species Klebscta species Proven species Providence spooks Serratia marcescens Ctrhacter species, Morganelta morgan Prewdononds gerginosa Hoemopats inuencae ‘Moraslla catarrhalis ‘Anaernbes Clowraium perfringens ‘Other pathogens Legionella prenmophite Mycoplasma preamoniae Chiang peieniae “Anaerobes {ronan species Eubacteriun species Pepwococeus spies Peptostrptocnecus ‘ecies acterides fags Fucobacteria species D. Antibiotic Class: Sulfonamides SeiFON OBES Sulfamctioxazole Sultmettonazoe pus trimethoprim ‘Sallisoxazole Gram-positive Sweprecoceus, Gram-negative Escherichia coli ici Agertsenarven 202 1434009 oe ‘W.Nuetole Acld-Rotve Antbiotios ‘-Anibiot Glass: Suflonamides Klebsiella species Enembactrspcles Morganelia morganit Protas abi Protes vulgaris ‘Shigella species Hoemophulus fence Other pathogens Presomocyts five Sulfadiazine plus Toxoplasma gon peramethamine Plasmedivn species SBI evi spesnum beta atau: MRSA, methine Sepa oar “Rn fos the ed aria sessile however ome rake sit he ogy mye es cepa or essa toch ee ages se Shnepltiy ptr for eck yatinen an an my be could © psione tog oes ean Flan xooens exe Natural Penicilins [Natural ponicilins are the natural products of Penciltum chrysogenui. Ie is likely that penicillins evolved millions of years ago as result of competition for survival berwveen single-cell organismns.* Fleming's ‘observations in the 1920s led to the identification of penicilin, and the discovery of the mechanism by which Penicilium killed other Dacteria paving the way forthe meer era of antibacterial therapy. ‘The basic structure of penicillin, 6-aminopenicillanic acid, is ‘characteristic of the lactam ring fused to a larger fing stucture (0 reste a penam nucleus that i the basie structure of all penicillins (see Figure 292-2). Of the natural penicillins, only penieillin G (crystalline penicilin G, beneyl penicillin G) and penicillin V (pheooxymethy- penicillin) are currently. available commercially. Peniciliin Gis Available in both oral and parenteral formulations. For inamuscular injection, pencilin Gis also available in repository forms ofthe crus, Procaine penicillin G and henzathine penicillin G both have much longer serum elimination half-lives as a result of prolonged absorption from the muscle injection ste, compared with crystalline penicillin G- However, the peak serum concentrations of the repestory forms of penicillin G ate considerably lower than those achieved with Intravenous administration of crystalline penicillin G. Therefore, the only situations in which the repository forms of pencilin are effective are those in which the organisms are exquisitely susceptible to Penicillin, in tissues with good perfusion, For those receiving com- parable mg/kg dosages, procaine penicillin has a halflife of “approximately 12 hours and achieves peak sorum concentrations of about 2 pgimL, compared with a half-life of 30 to 50 minutes for rysalline penicillin G, and achieved peak serum concentrations of approximately 20 ug/ml. Benzathine penicillin G yields even lower Serum concentrations (only about 1S jgimL), but may nemain above 10.2 jgiml. for 3 weeks or longer. Combinations of procaine and benzathine penicillin, either in equal amounts, or as a 3:1 (benzathinesprocaine) mixture are aso zvallable Taeclinical practice, although active against a wide range of bacteria. (see Table 292-2), the natural penicillins are most widely used for freatment and prevention of infections caused by streptococci Pharyngitis, lower respiratory tract infection, skin and skin structure infections, and bloodstream infection (BSI) caused by group A streptococcus (Sireprococcus pyogenes) are effectively treated with penicillin, The in vito susceptibility ofthese organism has remained ‘unchanged over the past several docades," although the efficacy in the treatment of steplocoocal pharyngitis in more recent studies is less than expected, for reasons that are not known." IntramuscularGRAM-POSITIVE BACTERIAL CELL WALL _ 7 ote ais Aninizoia pnts cnarren 202 13008) Figure 292-8. Scie of acta ool walls of (g3-postve and gram-negative Dacor ‘Cytoplasmic membrane GRAM-NEGATIVE BACTERIAL CELL WALL = Sconce | = rt Cytoplasmic ie Functional protein ‘thin membrane @ Nacatyitucosamine @ Nacetyiruramic acid parenteral and oral formulations. Recently, with the emergence of ommunity-associated (CA) MRSA, their long-standing role in the empiric therapy of presumed staphylococcal infections is. now ‘compromised. For susceptible sans of S. aureus, however, thy femain among the safest and most effective therapeutic. agents svalabe ‘Aminopericilins ‘This class of semisyatbetic pencils contains an amino substitution inthe phenyl acetamiso sie chain ofthe penam micies, providing & Polar charge on the molecule that allows antibiotics of this class to demonic sotivty against gram-negative pathogens, including Escherichia coli and Hocmoplilus influencae (see Table 292-2) However, tis cliss of antibiotics isnot stable to the staphylococcal peniclinases, or to the hundreds of different bet-lactamases that sram-negative pathogens may produce. The activity against other trampositive organisms, seh as group A and group B streprococ! Js still very good, and activity against most enterococci i equivalent {© or beer than pencilin G ‘As a means of enhancing the activity of the aminopencilins against bea-lactamase-producing pathogens, the concument use of & Second beta-lactam agent tht binds irreversibly to a pathogen’ bets- Tactamase has led to success in the therapy of infections caused aetam anubvoue, ‘st anueroes, wiun Ne exception OF Dets-eTAMase-produeing strains of Bacteroides sp, and Prevotela sp. are highly susceptible 10 Tn clinical practice, these antbiotes are used to treat infections penicilin G, However, due to the common presence of Buacternides ‘caused by susceptible strains ofS. aureus. They are avaiable in both PART IV Laboratory Diagnosis nt Therapy of fects Dsesesproxlueed most commonly by Escherichia coli and Klebsiella sp.!"The activity ofthe third-generation agents is superb against virtually all strains of H. influncae. These agents, in general achieve CSE concentrations that are elective in weutment of bacterial meninits caused by all three major pediawe pathogens: H. influenzae, Step tococeus pneumoniae, and Neisseria meningitidis. OF note, certain penicilinresistant strains. ofS. pneumoniae have’ decreased susceptibility to these cephalosporins and have been associated with clinical and microbiologic failure at tissue sites with decreased antibiotic penetration, such as the cental nervous system (CNS)." "7 Howeves, the most active ofthe thi-generation capbalosporins against S. pneumoniae, ceftriaxone and cefotaxime, have not been associated with treatment fae of respiratory tact infections caused by peniclln-esstamt strains when appropriate dosing regimens are used. None of the think-generation agents should be considered ‘optimal for the weatment of infetions. caused by Staphsloenccus ‘aureus ss other cephalesporins and penicllinase-stable penicillins are more ative against this pathogen ‘Of the thie-generation agents, ceftriaxone has a prolonged serum halite compared withthe other agents, allowing for its once-daily use. The infrequent dosing and the ability to use either intramusculae or inravenous routes of administration have allowed for outpatient therapy of serious, invasive infections at & point when the child's condition is stable ‘The founti-genecation cephalosporin cefepime, maintains activity against Pseudomonas aeruginosa, displays enhanced stability to the amipC chromosomal bet-actamases of Enterobacter, Serratia, and Cinrobacter species, while retaining. significant (but not optimal) activity against Stapholocaccus aureus (see Table 292-2). This broad activity allows for empin therapy of neutropenic children with fever, and allows fr sreatiet ofa wide variety of nosocomial gram-negative infections." However, lack of activity against beta-actamase- Posive stains of Bacterides fragilis and. against Enterococcus Timi the ability to wea intra-sodominal infections using this single agent ‘The fifth generation of cephalosporins, still in clinical wal, combines the activity of the thid- and fourh-generation cephalo- sporins with the fist documented in vitro aetvity of any beta-lactam agent against CA-MRSA. These agents have been designed to bind to and inactivate PBP2a, which eonfers resistance in MRSA to all other currently avaiable beta Carbapenems ‘These agents, also naturally occuring, were initially isolated from a species of Streptomyces, with the beta-lactam moiety contained within 4 earbapenem nucleus (See Figure 292-2). They demonstrate the broadest speetrum of activity of all ofthe beta-lactam antibiotics and currently Include imipenem, meropenem, and ertapenem. They are active against both gram-positive pathogens, including staphylococci tnd steptococe! (with moderate activity against ampicilline susceptible enterococe), and gram-negative pathogens, including P. aeruginosa for imipenem and meropenem, with enhanced stability against both the chromosomal ampC bets-iactamases of Enterobacter, Serratia, and Citrobacter species and the ESBLS of F. coli and Klebsiella (see Table 292-2). They are highly active against anaerobic organisms, including beta lactamase-producing stains of Bacteroides ‘and Prevotella, OF these agents, the antibacterial spectrum of activity Of imipenem and meropenem is similar, whereas ertapenei matches ‘he activity against enteric bacili, but is not as potent against Pseudomonas aeruginosa. Iipenem is pated with clastatin, a renal ‘dehydropeptidase inhibitor that inhibits the destruction of imipenem by renal tubular enzymes providing both an inerease in the secum hal life of imipenem and a decrease inthe renal toxicity ofthe compound. Imipenem use was associated with unexpected seizures in an open, ‘oneomparative clinical tral in children with meningitis, probably attributable to competitive inhibition of the inhibitory CNS: neural pathways. Therefore, meropenem, which does aot produce clinically Avni gens cnarren 292 1435/0008) detectable CNS side effects, is the prefered earbupenem agent for treatment of CNS infections, including meningitis, brain abscess, ‘epidural abscess, and subdural empyema. Ertapenem has the most prolonged serum half-life of the carbapenems, and requires only once daily dosing in older children (13 years of age) and once- or Wice-2- «day dosing in younger children, These agents ace all used primarily fr fosocamial infections or infections in immunocompromised. hosts ‘when the exceptionally broad spectrum of activity is essential, Data support clinical and microbiologic efficacy in poeumonia, UTIs ‘wound infections, bone and joint infections, and skin and skin structure infections. Imipenem and meropenem are reasonable Single-drug empiric therapy of fever and neutropenia. in immuno ‘compromised children,” As with the laier-generation cephalosporins, they provide good, but not optimal, activity against Staphylococcus ‘aureus, They provide the bes activity af al beta-lactam agents against Dpithogens harboring either chromosomally mediated ampC beta Tactamases or ESBLS. In akltion, single-agent therapy of appendicitis hhas heen documented to be effective, and allows forthe possibility fof convalescent outpatient therapy." Use of such broad-spectrum agents must be weighed against the risk of promoting resistance and profoundly altering normal fora. Monobactams ‘This unique beta-lactam structure isa naturally occurring antibiotic isolated from Chromobacterium sp. its not fused to an adjacest ring. ‘Aztreonam. the only available agent in this class. has been highly modified chemically with side chains. and demonstrates grant negative activity comparable with the third-generation cephalosporins but without significant gram-positive or angerabie activity, Clinical use in pediatrics is limited, and cccurs primarily in communiy- Acquired infections in which enteric gram-negative organisms are suspected or proven pathogens Glycopeptide Antibiotics ‘This cass of antibiotics interferes with cll wal formation in the steps that erate the plea chains prior to crosslinking the chains in the Formation of pepidosycan (ste Figure 292-1. These ambitis have 2Targe, complex sructure tht consists of multiple peptides linked together ind three rings, with various side-chain substations inclung lage saccharide moities atached to the ental pulseyclic structute, Strong hydrogen bonds occur between the glycopeptide antibiotic and the terminal Dlanine, D-lanine dipeptide of the pentapeptide side eats of he MurNAé subunits of the glycan chain Once Bound, the glyeopeptides sterically prevent the ans lycosplation steps roquifed for lengthening the chain and the Subsequent cros-inking Glyeopepie sabi are primarily fetive against gram-positive organisms, in which the cell vall Construction accurs outside the ell membrane (see Figure 292) Lite activity is demonstrated against Gram-negative organisms, 3s the Tange structure does not easily cross the gram-negative outer membrane, preventing contact with enzymes responsible for transelyeosyation in the periplasmic space. Recent documented resistance in gram-positive pathogens to vancomyein as Ted To incense investigation of derivatives of vancomycin and tichoplania, a lycopeptie antibiotic available outside the United Stats Vancomycin Vancomycin is a natural produc, originally isolated from Streptomyces sp. in 1956, Vancomycin isthe only glycopeptide curently avaiable in the United States. Originally developed to treat staphylococcal infections, vancomycin was rarely used following the availability of the penicilinase-sable penicillins, which were better tolerated. However, with the first appearance of healthcare-associated (HA}-MRSA four decades ago, vancomycin played a continuing role[E436 seerio B Artec Meraoy in the treatment of nosocomial Staphylococcus aureus infections. Recently, with the increasing prevalence of CA-MRSA, vancomycin is ‘ow routinely used in the empiric therapy of serious and ie~ threatening staphylococcal infections, ‘Some concer exists for the degree of bactericidal activity and clinical efficacy demonstrated by vancomycin compared with the Penicillinase-stble penicilins for weatment of MSSA. Based on these considerations and greater toxicity of vancomycin compared ‘with betalactam agents, vancomycin isnot generally the preferred therapy im infections caused by MSSA. Newer slyeopepties and lipopeptides |huve show inreased in vitro activity against S-aurews compared with vancomycin, although prospective, controlled clinical data t0 document, improved outcomes se not available, particularly for children 72" Resistance 10 vancomycin has developed in several ways. In Enterococcus sp, sand resistance, that leads t0 viral complete resistance to vancomin, occurs witha ransmisible seo? genes which encode a series of biologic functions. These genes allow Enerococes (0 sense the presence of vancomyein, to cleave the Dealanine, D-alanine Aipepide om the pentapeptide chain, and to subsite enzymatically b alanine ota a the eins ofthe penapephie resting in G0. fold decrease in binding of vancomycin" The new pentapeptide appears to be as viable a precursor for pepeidol yea formation the ‘original pentapeptide. inemPenecus also has less common mechanisms of resistance. The vand resstnae mechanism has now been detected in 4 adult patients with sphylococeal infections, crating vancomycin. resistant S aun (VRSA) A more common resistance mechanism OF 5. aureus to vancomycin, producing intermedistely susceptible sins of ‘VISA, is proliferation of the D-alanine,n-alanine elyean structures in & Aisoxganized, thickened eel wall, leading 10 increases in the binding and trapping of vancomycin to nonfunctional dipeptides" Unde ‘aucomyein pressure, these rains, which ae present within every large Population of staphylococci, are selected out. This mechanism of resistance, to vancomycin, called hetroesistance, is either sable or unstable? ‘Taree new glycopeptide antibiotics, dalbavancin, tlavancin, and ‘oftavancin, have demonseated clinical efheaey in small clinical tals, but none is yet approved for use. Modifications of the glycopeptide to enhance binding to targets, co increase sabilily of antibiotic binding by creating glycopeptide dimers, and o anchor the glycopeptide tothe cell membrane have all been suecessful strategies at enhancing the activity ofthis las of agents, Clinical uses of vancomycin include therapy of gram-positive infection in children who are penicilin-allergic, therapy of infections caused by Sirepiococeus pnewnoniae that are resistant peniili.* ann therapy of infections caused hy MRSA. Treatment of Clostridium dificil infections with orally administered vancomycin is highly effective, but it has not been recommended Tor te past decade di to the emergence of vancomyecia-resstant entracocel (VRE) following therapy. ‘However, in selected cases of metronidazole failure, ‘vancomycin represents eflecivealtemative therapy. A common reaction may ogcur with the rapid infusion of vancomycin, the red-man of red-neck syndrome, characterized by Musing and hypotension. This reaction is hstamine-mediated and not immunoglobulin E-mediated and is distinct from anaphylaxis. The risk of this reaction varies dieety with the rapidity ofthe vancomycin infusion; therefore each dose of vancomycin is usualy infused over ‘Thou. For children who develop this reaction, prolonging the infusion ‘or preteating with antihistamines may allow continuation of therapy ‘with vancomycia, Cell Membrane Active Antibiotics Daptomycin Daptomycin, « natural product derived from Streptomyces spa is & nove ipopeptie antibiotic thts rapidly bactericidal hase on effects fn the gram-positive cell membrane. It has unique stricture that consists of 13 amino acids, with 9 pepaides inked together ina rng sinieture, attached toa. lipophilic tail that insets into the cell ‘membrane. The mechanism of action of daptomyein is not well "understood, but it sppeas that depolarization ofthe membrane occurs 8 the antibiotic polymerizes within the hacterial cell membrane, Droducing channels in the membrane that result in leakage of cll contents. inhibition of protein, DNA and RNA. synthesis, and cell ‘death, Daptomycin is one of the most rapidly atercial antibiotics against Staphylococcus aureus based on in Viteo asays.® I is active fon @ wide variety of gram-positive onganisns, including MSSA, MRSA. VRSA, sirepiocoec, and enterococci Cinchuding VRE) (see Table 292-2) Clinical use of daptomyein has focused on MRSA infections that are unresponsive to vancomycin. Efficacy has been demonstted in ‘adults for skin and skin stracture infections, and for BSL. Surprisingly. ‘dapcomycin is not effective for the treatment oF pneumonia, based on clinical tials in which response rates were not equivalent to ‘comparator agents, and in which relatively low concentations of daptomycin were found in bronchial-alveolar epithelial lining fluid and lung parenchyma.” No pharmacokinetic or clinical study hasbeen reported in children, The prolonged half-life in adults of 8 40 9 hours allows for oace-RNA and ribosomal proteins. Several sites have been documented t be antibiotic targets on each ofthe subunits and at the junction of the subunits, Targets include: the entry site of MRNA, the intial cocognition and binding site of RNAS, the site of attichment of the IRNA-peptide chain where peptide bonds are formed (the peptidy! transferase center), and the exit channel of the growing polypeptide." The critical chemical and structural relationships between the ribosomal rRNA and the peptidyl transferase center, which promote the chemical reactions to ereate & ‘new peptide, as well as movement of mRNA and the newly formed peptide trough the ribosome provide opportunities for interference in bacterial protein synthesis Macrolides: ‘The currently available macrolides consist of the erythromyeins, azithromycin, clarithromycin, and telithromycin. All share structural Similarities which elude a 14-membered lactone ting (erythromycin, clarithromycin, telithromycin) or 15-membered ving (azithromycin), all of which bind to atleast one site in common within the peptide exit tunnel of the ribosome: domain V of the 238 RNA within the SOS subunit. Binding to a specific adenine residue of the RNA, 2058, ‘within this channel provents the ordetly movemtent of protein out of| the ribosome.” Clarithromycin is structurally very similar to erythromycin, with ‘only the addition of a single methyl group to the erythromycin ring, primarily conferring improved stability to gastric acid. Whereas erythromycin, clarithromycin, and azithromycin contain a cladinose carbohydrate atached to the lactone ring, telithromycin substitutes a ketone in this position (hence the name, Ketolide) while adding highly charged side chains to the C11 and C12 positions. These changes improve the binding characteristics to both the peptide tunnel binding site within domain Vand ereate an adctional unigue binding site at adjacent domain II within the ribosome, improving activity against many macrolide-resistant gram-positive organisms. Azithromycin is sSructurally similar to erythromycin, but contains a 1S-membered (rather than 14-membered) ring withthe addition of a nitrogen atom within the ing isef,strcturally changing the dug from a macrolide to an azalide, but containing the same side chain-attached ‘arbohydate moieties as erythromycin, This change improves gram- negative activity as well as increasing gastric acid stability. The degradation products of azithromycin provide far less stimulation ‘of gastric motility, improving the tolerability of azithromycin over erythromycin, In general, the macrolides arc inhibitory to bacteria, not bactericidal, and therefore are ot commonly employed in the treatment of serious and life-threatening infections. when other Iactercidal agents can be used, The various macrolide agents have Antimicrobial Agents CHAPTER 202 1497/0) fereot binding affinities for their sibosomal targets in different ‘organisms. The binding is generally reversible, with amore prolonged rte of dissociation of the ribosome potentially aking to a more poknged postanibiotic effect seen with some macrolides (Table 289-1) ‘The macrolides are most active against gram-positive cocci and baci, and, to a lesser extent, gram-negative bacill (see Table 292-2. Some of these agents are also active against spirochetes and certain ‘myeobacteri Pathogens that Tack a formal cell wall and are not susceptible to beta-lactam antibiotics often remain susceptible 10 ‘macrolides, including Mycoplasma and Uveaplasma species ‘All of the macrolides achieve high intracellular antibiotic ‘concentrations within phagocytic cells. These concentrations are often ‘much higher than those measured in serum, providing acess ofthese anibioties o infected tissue spaces by means of neutrophils and establishing higher tksue concentration than antibioties that eter ‘primarily by diffusion alone. However, much of the macrolide is ‘resent in an intracellular locaton, allowing less free drug available ro expose extracellular pathogens. Due to high intracellular concen- (vations, the macrolides are particularly effective therapy against susceptible intracellular pathogens In general this class of drugs is well tolerated. However, the gastrointestinal side effects of erythromycin may be problematic in some children, Clarithromycin, azithromycin, and telitomyein are all beter tolerated than erythromycin. With the exception of azithromycin, this class of antibiotics is metabolized by’ hepatic cytochrome P-450 system, and drug-antibiotc interactions should be considered as they may increase or decrease the macrolide and concurent drug concentrations. Azitheomyein has demonsrated ‘minimal drug-drug interactions, and may represent the preferred ‘macrolide in eetain situations, paicularly for immunocompromised children recsiving multiple concurrent medications "Not surprisinaly, resistance tothe macrolides is documented when ‘molecular changes oevur at the critical ribosomal attachment site, ‘most commonly a mono- or dimethylation of the A20S8 adenine binding site. The methyltransferase enzymes encoded by gram- positive organisms are most often inducible, but may be constitutively produced, leading to high-Ivel resistance to erythromyein,clarithro- ‘mycin, and azithromycin, and decreased susceptibility fo tlithro ‘mycin, Less frequeat alteration at this site also impact binding, with either substitution of guanine for adenine, o structural changes inthe LA ribosomal protein." Efflux pumps represent another common, ‘mechanism of resistance in. gram-positive pathogens, including [pneumococeus, group A streprocoecus, and Staphylococcus aureus ‘The most common pumps are alive against erythromycin, clrithro- mycin, and azithromycin, whereas most ofthe strains harboring these ‘pumps remain susceptible to telithromyein. = Erythromycin Erythromycin, natural product isolated fiom Succharopolyspora enthraea (formerly Streptomyces) in 1949, was first approved for Clinical use in 1952. Erythromycin is degraded by gastric eid, and has Tong been associated with stimulation of motiin rooeptors in the stomach and possibly in the colon, leading to adverse gastrointestinal side effects, including cramping and diarthea."** Many preparations have attempted 10 bypass exposure of erythromycin to gastic acid, thereby avoiding products of macrolide hydrolysis. These preparations include enteric coating of orally administered tablets, delayed-release {ormulations, polymer coating of beads, and various formulations of salts and ester" The lactobionate’ salt used for intravenous administration of erythromycin can produce phlebitis atthe site of injection. Erythromycin is used for the treatment of group A streptococcal infections in children who are pencilin-allergc. Erythromycin is an alternative treatment for both streptococeal pharyngitis and Streptococcal or staphylococeal impetigo. The clinical use of erythromycin for respiratory tract infections cause by Streprocaceus rewnoniae has been greatly diminished by the development of ‘widespread resistance to the macrolides." Empiric therapy of upper[i t68 seeri0n Bsa sey respirtory act infections (otitis media and sinusitis) of lower respiratory tract infections (pneumonia) potentially caused by 5. ‘pneumoniae has a relatively high likelihood of failure, particularly in ‘younger children who are at risk of infections eaused by antibiotic resistant strains. For upper respiratory trat infections, erythromycin has inadequate activity against H,infuensae, and mas be paired with nother agent such as a sulfonamide for empiric therapy. Macrolide therapy for atypical pneumonia caused by Mycoplasma pneumoniae, Chlamydophila pnesononiae, oF Legionella pneumophila remains effective forthe vast majority of these pathogens Erythromycin and avthromyein are the prefered antibities for treatment of Campylobacter gastroenteritis, Erythromycin also remains the most appropriate therapy fr diphheria (Corynebacterium diphtheriae). Eryhvomycin, clarithromycin, ot azithromycin Is recommended for treatment or prophylaxis of pertussis (Bordetella persis), Azitomycin is preferred for weatment ot prophylaxis for pertussis in neonates, based on concerns for the development of pyloric stenosis.” Etficaey of erytheomyein has also. been demonstrated in infections caused by Chlamydia trachomatl including neonatal conjunctivitis and pneumonia, as well as urogenital infections during. pregnancy. Erythromycin is also active in vito sgainst Ureeplasma ureaipticum, but the role of erythromycin inthe tteatment of neonatal respifatory tact infections caused by this onganism is not well defined. Ceritromycin With the improved activity demonstrated apainst H.influensae and improved wlerability compared. with erythromycin, teatment of respiratory tract infections is the most common clinical use for clarithtomycin. Food and Drug Administration (FDA-approved indications include pharyngtisionslits, acute otis media, acute ‘maxillary sinusitis, and community-acquized pneumonia eaused by susceptible stains of. peunoniae, H. influenzae, Moraxella eat. rhalis, Mscoplasma pneumoniae, Chlamydia pneumoniae, and Legionella preumephile. For, pneumoniae, stetns that are resistant to erythromycin from either methytranferase oe efflux mechanisms ate also resistant to clarithromycin. The activity of clarithromycin against H. influenzae is only moderate, but in noninferiority tals of clarithromycin in the ueatment of respiratory tract infection, the microbiologic and clinical efficacy was not significantly less than that tether approved agents Clarithromycin is one of the most effective macrolides for treatment and prevention of disseminated: mycobacterial infetions due to Mycobacterium avium-intracellalare complex. (MAC) ia human immunedefiieney virus (HIV)-positive hosts, Althoug Well studied in normal immunocompetent children, clarithromycin may play a role in the treatment of cervical adenits and pneumonia ‘caused by MAC (or other nontuberculosis mycobacteria proved to be susceptible in vitro, in conjunction with ether antiboties andor surgery Catthromycin also plays a role in the teatment of Helicobacter pylori infections (the. primary cause of duodenal -uleers) in Combination with amoxicillin and lansoprazole, or omeprazole, or in combination with ranitidine.” Clarithromycin has demonstrated efficacy similar to erythromycin in. pertssis infections in sina clinical wals, and is considered as one of three first-line drugs “Although approved for teatment of skin and skin structure infections, faritiromyein is not often used for this indication as other moe co effective or more active agents are available in the treatment af infections caused by Staphylococcus aureus, Similary, other beta Jactm and macrolide antibiotics are preterred forthe teatment of streprococeal pharyngitis, aithromyein Acithromyein has among the highest intracellular concentrations of the macrolides and provides the tost prolonged tissue concentrations at ihe site of infection allowing the antibiotie to be provided for very PART IV Latoratay Diagnosis and Tray oi short courses for respiratory tract infections. The activity against Streptococcus pnewnoniae %s similar to erythromycin and clan ithromycin. Enythromycin-resistant stains of S. pewanoniae ae also resistant fo azithromycin. Activity against H. nfluenaae is moder, with inneased activity invite compared with erytheoma, but with decreased in viteo activity compared. with clarithromycin and telthwomycin. However, the impact of relatively small differences in suscepiility in vitro is likely to be offset hy higher concentrations of antibiotic at an intracellular sit of infection. Azithromycin is also ative “aginst the pathogens causing atypical pneumonia (see Table 92-2), ‘Azithromycin is far beter tolerated than erythromyein, and can be given once daily and comes in both orl and intravenous formulations Based on noninferiority clinical wials, azithromycin has. heen approved for treatment of streptococcal pharyngitis, cite otitis media, Sinusitis, and community-acquited pneumonia in children Because of prolonged tissue concentrations, particularly using larger azidomycin dosages, S-day, 3-day, and 1-day treatment courses have been shown ‘o be comparable for clinical and microbiologic outcomes to L-day tteatment courses of comparator heti-lactam antibiotics in atte, uncomplicated otis media. However, as the dosage increases, the gastrointestinal tolerability f the antibiotic decreases, with vomiting and diamthea occuring in about 10% of children receiving 30 mglke a8 single dose.” Although clinical data on single-dose treatment ‘courses for otis media are available, data exist only for weatment ‘courses of 3 and $ days for sinusitis, and for 5 days for treatment of ‘community-aequied pneumonia and streptococcal pharyngitis. The dosage for treatment of streptococcal pharyngitis is 12 mg/kg per day ‘once daily for 5 days, which is larger than that for etts and provides ‘total dosage of 60 mike for this infection ‘Azithromycin has the widest use in children in the weatment of ‘upper and lower respiratory tract infections." However, other Uses Ihave been documented in clinical wal, although FDA approval for many of these infections. has not been requested, Treatment of pertussis as beem shown to he effective in small trials Based on eoncerns for pylori stenosis caused by erythromycin in young inf, avithnomyein is the recommended macrolide therapy or prophylaxis for infants under 1 month of age and is considered on an el Tooting ‘with erytiomycin and clarithromycin in older individual.” Arithromyein is also used in the teatmentof sexually transmited Infections, including Chlamydia machomatiscaused infections (orethrtis, cerviiis, and Iymphogranuloma venereum). chineoi, sranuloma inguinale. and gonortea." Similar o clarithromycin, azithromycin has been shown to pay a role inthe prophylaxis ad therapy of MAC infections in HIV-positive persons! Avithromycin may also have a role in therapy of cutaneous nd Iymph node infection eaused by these pathogens in normal chien ‘Azitiromycin has enhanced activity compared with the other macrolides against many gastointestinal pathogens, including Excherichia coli, Salmonella, Shigella, and Campsobacter® in vito activity demonstrated agains! Sabmomella is particularly advantageous en the iniracellular locaton of the pathogen in this infection.” With Widespread resistance among. gastointestinal pathogens. t belt Jactant antibiotics, fluoroquinolones, an trimethoprim sulfarethona- zoe in certain parts of the world, the uty of emit therapy of traveler's diarrhea with azitromyein has increased” ‘Azitromycin is the only antibiotic that has been prospectively evaluated forthe treatment of eat-scratch lymphadenitis caused by Bartonella henselae aud is one of the preferred therapies for this infection However the clinical response to eaten of Iymph node disease is not dramatic, and azithromycin has not been evaluated Drospectvely for the treatment in other Tissue sites of infection, such as lve, bone, or CNS. Telithromycin ‘elihtomycin, a semisynthetic macrolide, has the same ring tractre as erythromycin, but wth the substitution of the clainose side ein With a Ketone group (enhances gastric acid stability), and with the addition ofa eyclic carbamate group providing a second link besween 5 leasesthe CLL and C12 positions of the ring. In addition, a long alkyl-aryl extension side chain has been added c the lactone ring, which provides for two additional binding sites for telithromycin to the Fibosome, The Ketone substitution also appears to. prevent the induction of methyltransferase activity that has been associated with ‘iono- or di-methylation ofthe primary macrolide binding site inthe peptide tunnel and loss of antibiotic activity of other macrotis.” As a result, telithromycin has improved activity against. many enythromycin-resistant strains ofS. pneumoniae and group A strepto- coccus compared with the other macrolides. However, telithromycin has only moderate activity against. influenzae strains, equivalent to clarithromycin, Like clarithromycin, in elinical trials of respiratory tract infections designed to demonstzte noninferiority, telithromycin was statistically similar to. comparators. (amoxicillin, eillin/clavulanate, carthromycin, or cefuroxime). ‘An unusual visual side effect of telithromycin, a decreased ability to accommodate visually and to release aecommodation, may affect up to 2% of cestain population groups. For these Tew people, itis rlomentarily difficult t0 focus on distant images if one has been focusing on a close image. and vice versa, AL present, limited pharmacokinetic, safety, and clinical efficacy data exist in children and the antibiotic is only FDA-approved for adults 18 years of age and older Tetracyclines The tetracyclines were also originally derived as natural products from Strepiomyces spp, with discovery in the 1940s and subsequent availa bility of to agents by 1948, chlortetracycline and oxytetracyeline."” The tetracycline antibiotics bind reversibly to the ribosome a the accepiar site (A site) where the amino acid-charged {RNA binds to the ribosome immediately adjacent to the site onthe ribosome holding the RNA strand. "The ttminoacyl tRNA binds together at the A site with an elongation factor (EF-Tu) and guanosine triphosphate (GTP), which spplies the energy required to drive protein synthesis, The protein Synthesis step includes the chemical rection to attach the amino acid to the growing peptide chain, together with changes in the conformation of the ribosome that ace associated with movement of the protein chain and the mRNA through the ribose, followed by the subsequent release ofthe “empty” tRNA." Itappears that the Mat, fourring structure characteristic ofthe tetracyclines binds at least ‘wo locations within the ribosome. Binding at the classically recog: nized A site appears to prevent movement ofthe ¢RNAJmMRNAVEF Tu complex into the “P site” (peptidy! site) by steric hindrance, which prevents elongation ofthe growing peptide. Binding to a second site in the 30S ribosome may stabilize the sbosome in an inappropriate ‘conformation a the erucal site of recognition of the aminoacyl (RNAS lamicecon with the corresponding eovlon within the mRNA. thereby preventing placement of the correct amino acid in the elongating hain.” Tahibition of peptide formation by tetracyclines occurs after the binding ofthe tRNA to the complex and after expenditure of GTP= ‘mediated energy, presenting the bacteria with an energy cost in aadtion to blocking the synthesis of a new protein. The tetracyclines are effective against many gram-positive and ‘gram-negative bacteria as wel as against call wall deficient pathogens (Mycoplasma, Rickettsia) and certain single-cell parasites (see Table 292-2). Eukaryotic cells have elongation factors different than bacteria, and are therefore not susceptible to the protein synthesis inhibition activity ofthis class of antibiotics, The tetracyclines ae, in ‘general, buteriostatic due to the reversible nature of binding to the rbosome, The tetracyelines enter the gram-negative cell wall through ‘outer membrane porin proteins and are sufficiently lipephilic to allow passage through the cytoplasmic membrane ofboth gram-negative and ‘gram-positive acter Resistance to tetracyclines occurred quickly following their ‘aallability primarily based on eMlux pumps and, (0a Tesser extent on the presence of ribosomal protection proteins.” These resistance mechanisms are present on plasmids, conjugative transposons and Amtimirobial Agents: CHAPTER 292 inegrons, allowing free exchange of resistance determinants between ta wide ange of bacteria. Over 200 different efflux pumps have been characterized, most of which are active against tetraeyeline, some of which ae also active against minocycline, and Fewer sil also active ‘against tgeeycline. The ribosomal protection protein have sequence homologies with bacterial elongation factors present in the {tRNA/mRNA/EF-Tu complex. Ic is believed that, as these proteotion proteins themselves bind tothe ribosome, changes inthe conformation ft the tetracycline binding site occur, preventing the binding of tetracycline but not interfering with protein synthesis. Resistance at the second 305 ribosomal binding site has also been described, due to base substitutions in the FRNA of the 308 unit ‘Advances inthe design of the structure ofthe early tetracyclines, Jed to doxyeycline (i 1967) and minocycline (in 1972), bath of which provided. a greater spectrum of activity and improved solubility, treating improvements in both oral and parenteral preparations (see Table 292-2), Doxycycline and minocycline may be taken with food (vith the exceptions noted below), as the absorption of these drugs is not significantly deeveased with meal. In most cases, doxycyeline and minocycline demonstrate increased activity against gram-positive Crganisms, and deereased neivity against gram-negative organisms compared with tetracycline. Activity against Enterococcus faecium, bout not E. faecalis, was achieved with newer agents. Minoeyclne, however, demonstrates. improved activity against. gram-negative “organisms, including Haemophilus influensae, Moraxella catarrhalis, Escherichia coli and Klebsiella compared with tetracycline, but only fair activity against Salmonella and Shigetia spp. and Psewdomonas aeruginosa, Tigecycline inereases the spectrum of activity agaist ‘many enteric gram-negative bacilli and anaerobes, including Bactervides fragilis, but sil lacks 2 high degree of aetvity aguinst P- aeruginosa (see Table 292-2) Historically clinical use in pediatrics has been limited by the binding of tetracyclines to teeth and bones in. growing children Permanent staining of the eeth (not affecting the stctural integrity of the tooth) and enamel hypoplasia oeeurs with any tetracycline ntbiotic, with the degree of staining directly proportional tothe number of tetracycline courses prescribed. A single couse of therapy is not associated with clinically detectable changes.”> " Stable calcium complexes can also develop in bone, and reversible decreases in ong-bane growth rates in juvenile animals have been observed. The clinical impact of these observations for children is not well defined but has been a cause for concer, limiting the use of tetracyclines 10 children 8 years of age and older." In addition, the tetracylines cross the placenia to expose the fetus; skeletal embryopathy in experimental animals has been noted. The oral tevacylines cannot be taken with Airy products due tothe insoluble chelation complexes tat form with calcium; similar complexes form with magnesium and iron ions, ‘When ingested with foods containing these ions, absorption from the ‘gastrointestinal tact is blocked In adults and older childten, the tetracyclines have been used for tne treatment of mild to moderate cespratory wact infections, skin and skin structure infections (most commonly sene), and sexually transmited infections. Some agents in ths elas demonstrate activity against strains of CA-MRSA” penicillin-esistant pneumococci, and VRE. and have heen used” in the treatment of these infections Horsever, few prospective, comparative data are available to assess the efficacy ofthis clas of antibiotics against these pathogens, with the exception of recent studies on tigeeycline Important infectious diseases for which the tetracyclines remain first-line therapy include infections eavsed by the Rickersia (most notably Rocky Mountain spotted fever, tularemia Coral therapy for Jess severe infections), brucellosis (with sfampin), cholera, chlamydia genital infections, and Lyme disease (Borrelia burgderfer) in older children Tigecycline cycline isa chemically mosified minocycline, with the addition of 4 ebutylalyeylamido side chain to the C9 carbon of the “D” tetraee cycline ring.” Tigecycline isnot affected by the majority of efflux pumps and ribosomal protection proteins which decrease the activity ‘of other tetracyclines. [thas a hiher binding affinity to the ribosomal binding site than the previous tetracyclines” and has a broader specrum of activity than any other tetracycline agent (see Table 92 2)-In at models, bone discoloration was documented, suggesting that ligecyeline forms calcium complexes in bone similar wo ober texracycline antibiotics. In adults, tgeeycline is approved for weatment of complicated skin and skin stucture infections and complicated ineaabdominal infections given it activity against enteric gram-negative bacilli and anaerobes, including Bacteroides frags. Tigeeycine retains activity against the agents of atypical pneumonia that is equivalent to, o better than, earlier tetracytine, ‘The ultimate clinical role of tigecycline has yet to be defined inthe tweatment of nosocomial infections caused by mulidrug-esstant sra-negative and gram-positive organisms that remain suscepaile to Uigeeycline. Fr children, the risks of bone toxicity and tooth staining reed tobe bulanced withthe benefits of therapy, particulary for drug resistant pathogens. For situations in which no alferatves exist, the tetracyclines represent effective therapy. Lincosamides The Tincosamides are naturally occurring compounds derived from Sivepiomyces spp. Clindamyein, approved in 1966 isthe only incos amide aailale in the United State and is semisynthete derivative Of lincomycin. The lincosamide amibioties ind wo the SOS subunit 2 site which overlaps bath the A. and P sites on the ribosome, preventing the docking of charged 1RNAs and their movement through the peptidyl transterase center, thus inhibiting the formation of protein, The P-ite attachment of clindamycin oceurs at the same Fibosomal structural bases as the macrolide binding sites (A20S8, ‘A205, explaining the competitive inhibition between binding ofthe two elases of antiotes for the ribosome, a well the resistance that ‘occurs to both antibiotics by altering a single base” The lincosamides fare generally considered bactriostai, although bactericidal activity ean be demonstrated against certain organisms at antibiotic concen tuations 2 tod times dhe minimum inhibitory concentration (MIC). Resistance 0 the lincosamides occurs primaily for bacteria constitutively producing. the methyltransferase that mono- of ‘imethyltes the A2OSS adenine present atthe outlet of the ribosomal peptidyl taferase center, This inducible enzyme is most often only setivated in the presence of the appropriate substrate, usually a macrolide, In contrast, de Tincosamides do net appear to induce the methylase enzyme. Therefore, organisins which have inducible resistance should remain soscepale to clindamyein, even following exposure 1 the antibiotic. However, genetiealy altered strung that constitutively produce methylase occur ata rate Of approximately one in 10" Stgphylococeus aureus organisms, raising the concern that for serious infections involving greater than 10" organisms, selection of Consitutive mutants may cccur during therapy, with subsequent ‘weatment failure.” The commonly encountered effox pumps tht are active aginst the macrolides are not active against clindamycin, High inacellular concentrations of clindamycin in phagocytic cally are believed to be beneficial in certain clinical infections.” However, no prospectively collected dats have confirmed the benefit in clinical or microbiologic cure of infection either as a result of Improved intracellular killing of organisms sich a staphylococci, o improved delivery of clindamycin to the site of infection through ‘phagocytic ell migration, ‘Clinical use of clindamycin has changed substantially over he past, decade. Tas commonly been used for its activity against anaerobes in the treatment of intra-abdominal infections such as appendicitis, although the percentage of srtns of Bacteroides fragile resistant lindamyein is increasing.” Deep head and neck space infections, and aspiration pneumonia (widh or without empyema, aso caused primarily by anaerobes and gram-positive ‘cose, continue ta be excellent uses of clindamycin. Less common uses in the past have ‘een for weatment of gram-positive coe, such as failures of penn in group A streptococcal pharyngitis, and for treatment of aureus infections in chien who could no tolerate beta-lactam antbisics, Inthe early 1990s, the emergence of penicillin and macrolide resistant Sireprococeus pneumoniae causing upper and lower respiratory tract infections promoted the use of clindamyein inthe ‘weatment of mild to moderate respiratory tract infections in children Although ‘no formal, randomized prospective comparative stdies ‘were performed in acute otitis media, sinus, and preumoni, clindamycin has been recommended for treatment of peniclin resistant pneumococci in these situations." Since the mid-1990s, with the dramatic emergence of CA-MRSA. ‘he use of clindamycin for skin and skin stractareinfetions and bone and join infections has also increased substantially. Although most published data on the efficacy of clindamycin in the treatment of MRSA are retrospective, clindamyein appears o be elective foe these pathogens." While some rogions of the United States in which MRSA is prevalent have documented decreasing resistance 10 clindamycin due to spread in the community of certain cindamycin- susceptible clones." other areas may experience increasing clindamycin resistance. ‘The ability of clindamycin wo target ribosomal proein production has led investigators 10 consider its use inthe teatment of toxin mediated infections caused by Staphylococcus aureus (oxi shock syndrome) and Sieptococeus pyogenes (toxic shock-like illness), either alone or in combination with cel wall active antibiotic agent In vitro data and reospectively analyzed human data suggest some benefit of combined therapy" ‘The principal adverse event associated with clindamycin i dices function ofits activity against normal snaerobie gastrointestinal flora ~ dianhea" Clostridium dificle-mesited pseudomembranous colitis is potential complication of virwally any broad-spectrum antic, including clindamycin, Accurate, prospectively collected data on te Incidence of C,dificte-positve enterocolitis ae not available oe cls ‘damycin- treated children, but increasing reports of enterocolitis hase not nccured with the increased use of elindamyéin for peumccocca ‘or staphylococcal infections Aminoglycosides ‘The aminoglycoside class of antibiotics is comprised of many antibiotics orginally derived from organisms, including Sirepomyees Pp. and Micromonospora spp. In general, these antbitics contain 2-deoxystrepramine ring attached 10 two or thee additional moieties, Tost often amino sugars, all connected together by plycosidic linkages. Substitutions at up wo 10 different positions onthe thre rings for their associated amino groups have led tothe eration of sever aminoglycoside antibiotics. However, given the nephrotoxicity and ‘totoxieity inherent inthe aminoglycosides, litle recent activity his ‘occurred inthe development of newer agents by the pharmscrnicl industry. All aminoglycosides current available in the United Sats are generic, with gentamicin, tobramycin, and amikacin representing ‘those ment often vised in ehldren, Al of the aminoglycoside antibiotics share a common binding ‘region within the 308 ribosome. This region is located atthe peptidy! transferase center where charged (RNAS are fist recognized and tach othe A site. With aminoglycoside binding close tothe A site Conformational changes occur atthe ribosomal (RNA docking site ‘which erates enhanced affinity for RNA binding, ineludingincoret binding of noncognate {RNAs which do not match the eoresponding codon on the mRNA. With atachment of incorest RNAS, misreading ‘eeu and amino acid sequences in the resulting peptide are income, Teading tothe cretion of nonfunctional proteins. With binding ofthe aminog_yeoside, proofreading forthe accuracy of the attached tRNA Js also compromised, as subsequent conformational changes that should occur in the 30S unit 10 allow for exact recognition of the tached tRNA cannot take pace." The structures of 0 of the larger aminoglycosides, streptomycin and spostinomycin, lle for PART IV Labora ares nd Therapy of nectous Dsesesddional binding sites within the 308 sibosome. Streptomycin attaches at four diferent domains within the 30S FRNA, as well as having a unigue attachment to one of the ribosomal prcins Speetinomyein, a laner strate with fused rings, appears Bid a {he A stein unigue manner which also blocks the meemest of the aminoacylARNA/peptiy] RNA/EF-Tu complex fom the A sito he P ste dating the pepid wansferase reaction. With the pructon of slmonmalprocins that may be incorporata into cellular siuctres such asthe cell membrane iereased permeability of the membrane cour. With increased permeability the aminoglycosides demonstrate hanced entry into the calls, allowing further saturation of amino~ lyconide binding sites on the ribosome, this preventing the formation 6f nen, funetonal ribosomes, which viimately results in cell death ‘The ainosycosides are bactericidal, and show concentration: dependent ling of bacteria Table 289-1). Resistance to aminoglycosides occurs primal with the acquis sion ofa variety of aminoslyeoside-maiyng enzymes, many of which ae caied on plasmids and transposons for efficent ypread between buceria, The most common are acetyiransfeass,adenyransersc, and phosphotansferases Many ciferentetfiux pump systems also Piya major ole in aminoglycoside ressance, pies in gram negative baci” Of imterest the Actinomyces species from which the aminoelyco- sides are derived contain resistance mechanisms tothe antbities they produce Ribosomal RNA methslase genes ofthis genus that confer Fesisiance 10 aminoglycosides were not believed to have clinical relevance, but have recently been identi in eiica isolates of enteric. gram-negative bacilli and Pseudomonas aeruginosa.” “Although ths mechanism of resistance is curently uncommon, these tenes mow have the potential o spread quickly wii linia eins. ‘The stiical se of aminoglycosides occurs. primarily for the treatment of gram-negative Tacllatve bailar infections ~ from the premature neonse through the adolescent” "The anibiotics ae Strongly polar, with high solubility in water, but with por solubility in Tipidsreakng in poor penetration into the CNS, viteous, bonchi secretions, and saliva, However, these antibiotics are concentrated in tho proximal renal tubules and exereted in urine and achieve urinary tral concentration up t0 100 times te serum concentration. Dus (0 the trict oF the aminoslycosides at serum concentations which ane onl 5-10 fold shove the bacterial MICS, they ae not usually Used as the Sole agents Tor ueatment of serious infections. The minogyeosies are frequently pred with a beta-lactam anibioi to create synergistic antibacterial seiviy and potently to retard. the temergence of antibiotic resistance, although the clinical impact of omiination sherapy bas. got been well demonstrated ouside the Jmmunocompromised host” Empiric and definitive therapy of eaty- and late-onset neonatal septicemia with gentamicin-contining combinations for enrie gram-negative infections is sl consiered appropriate three decades following the fis recommendations inthis age group. although well-controlled, prospective. comparative studies have not generally been performed:*"" Therapy of nosocomiel infections with aminoalycoside-comaining regimens is stl wccepble {in institutions in which nosocomial pathogens remain suscople 0 the aminoglycosides” In gram-positive infections, the aminoglycosides ad enhanced tracer Kling to cell wall active agents, pariculy inthe weatment of serious infections°* Enterocaceal infects are treated with !npiciln or vancomycin in combination with gentamicin in oder achive bactericidal activity. The combination pencil plas gentamicin, 90% bioavailability. Although rectal administration Yields approximately 70% to 805 bioavailability, this route of ‘administration has never gained widespread acceptance in children, Metronidazole provides excellent therapeutic concentrations in a wide range of tissue sites, including CSE, in which concentrations are very ‘lose to those achieved in serum." Although the serum elimination half-life is approximately & hours, early studies performed in adults, for FDA approval used 6-hour dosing regimens, which unfortunately remains the current FDA dosing recommendation in the package label. The observed half-life with oral administration appears to be loager than tht found for TV administration, for unknown reasons. For most, clinical situations, hased on the pharmacodynamics of antibiotic ‘exposure, dosing every § hours should be adequate. One of the meta- bolites of metronidazole that displays significant antibacterial activity has @ more extended half-life, averaging 11 to 13 hours, providing nother rationale for less frequent dosing Clinical uses in pediatrics focus on the treatment of anaerobic infections." Given the excellent tissue penetration characteristics of metronidazole, activity agains all susceptible anaerobes is achievable in most tissue sites. However, data from randomized, prospective inca wials may not be available for may sites of infections, For any infection that may also involve facultative oF aerobic organisms, additional antibities are necessary. Metronidazole is bactericidal for Bacteroides spp. and has been used extensively in the treatment of intra-abdominal infections, including complicated appendicitis, penetrating injury to the bowel, ‘and colitis. These infections often involve multiple susceptible anaerobic species, incuing B. fragilis. Other mixed aerobicianaerobic infections inelude deep ead and neck space infections (e., paraph- aryngeal abscesses, Ludwig angina) and nerotizing fascitsieTloits (e.g, necrotizing synergistic fasciitis, Fournier gangrene, omphalits). Closiridia spp. are also susceptible 9 metronidazole, and can be effectively treated when causing deep-tissue infections. Some penicillin-susceptible. anaerobic gram-positive cocci axe not Susceptible to metronidazole. Metronidazole, in combination with other antibiotics and proton ump inhibitors, is par of a treatment regimen for Helicobacter pylori- ‘mediated ulcer disease. In addition, some benett in the treatment of ‘Crohn disease may occur with metronidazole," as the antibiotic and ‘antiinflammatory properties ofthe agent may both playa role Given the excellent penetration into CSF and bactericidal capacity, metronidazole treatment of anaerobic organisms causing meningitis or ventrcults (uaumatic, posisurgical, of nosocomial), of weatment of anaerobic brain abscesses is effective. Prospective, comparative data to document these indieations are not available “Metronidazole can also be used for female genital tract infections, including bacterial vaginosis, and as part of antimicrobial therapy of pelvic inflammatory disease ‘One of the most common pediatric uses for metronidazole isin the ‘weatment of Clostridium difficile enterocolitis, Following the docu mented increases in vancomycin resistance of gastrointestinal tract, flora withthe use of oral vancomycin in adults for C. dificil colitis, metronidazole became the drug of choice in therapy for children as well as adults. Clinical response rates for C. difeile infection ste equivalent, comparing oral metronidazole therapy with oral vanco~ mycin therapy. Entamoeba histoltica wophozoites (but not eysts) are susceptible to metronidazole, allowing therapy for both intestinal and ext inestnal amebiasis including amebic liver abscess. Metronidazole is fone of the drugs of choice for treatment of Giardia intestinal infections and isan alternative teatment for Dientamoeba infections For sexually active adolescent females anc males, metronidazole still remains effective therapy for Trichomonas ineetions."[ais section B to.ntece Torey Sulfonamides (Single Agents or in Combination with Trimethoprim or Pyrimethamine) Sulfisaxazole, Sutfamethoxazole, Sulfadiazine ‘The sulfonamide class was one of the fist available antibiotics for ‘human use, but duc to widespread resistance in common hacterial pathogens after decades of extensive use, applications for this class of ‘agents are now focused in a few areas of remaining eflectivenss. However, for pathogens that remain susceptible 10 sulfonamides, either used alone or in combination with trimethoprim. these agents have a long history of efficacy with reasonable safety. Curent!y available sulfonamide agents are synthetic derivatives of the fist Ueseribed compound, sulfanilamide. At the time of discovery, sulfa agents were active agains staphylococci and a wide range of gram- regative pathogens. However, due toa high rate of resistance to sulfa agents when used alone, these agents are now alimest entirely used in combination with trimethoprim for the treatment or prophylaxis of bacterial infections. Sulfadiazine is currently used in combination with pyrimethumine forthe treatment of toxoplasmosis, but its no longer used to treat hactril infections. ‘Of historical interest, withthe success of sulisoxazole following its approval in 1953, many sulli-sulfa combinations and sulta- ‘erythromycin combinations were approved to take advantage of the diferent pharmacokinetic properties of the various sul agents, and the complementary antibacterial spectrum achieved with ther antibiotic classes. Trisultapyrimidines, or “tiple-sulfa” agents, contained sulfa drugs of varying serum elimination hal-lives (oulfuiazine, sulfamerazine, and sulfamethazine), whereas sult soxazole-eryihromyein combinations were active at that time against iis media pathogens, Streprococcus pneumoniae and H. influence. “The sulfonamides are bacteriostatic by means of competitive inhibition of para-aminobenzoic acid, utilized by dinydropteroate synthase inthe synthesis of dihydrofolic acid, a precursor of purine bases in the formation of nucleic avid. As bacteria synthesize folic seid, they are susceptible to this class of compounds. Sulfa agents are wel absorbed from the gestointstinal trae and are, in general, metabolized by the liver and excreted by the kidney. Both sulfisoxazole and sulfamethoxazole are highly protein-bound (70% to 80%), which raised concems about the use ofthese agents in ‘he neonate with hyperbiliubinemis, Due to sulfonamide binding to albumin, bilirubin may be displaced from its albumin binding sites, ‘causing kemieterus asa result of subsequent bilirubin binding to CNS tissue. Although sulfonamides may be contraindicated in il, acidotie infamts with hyperbilirubinemis, no cases of Kemicteris have buen documented in fullsterm, well-appearing. infants. Despite FDA labeling cautions against the use of this class of agents in infants under 2 months of age they are safe in nonacidote tern infants as ealy as the second week of life, as physiologic neonatal jaundice is resolving An intense immune-meststed separation of skin at the dermal ‘epidermal junction that may also insolve separation ofthe respiratory and gasirointestinal tact mucosa Ts the most severe hypersensitivity reaetion to sulfonamides. Variously called Stevens-Johason syndrome, toxic epidermal necrolysis or erythema mukiornie majo, the spectrum of reactions varies from a cutaneous blistering rash to severe, extensive. life-threatening sloughing of skin respiratory tract and gastrointestinal tract mucosa." AL the fist sign of a skin reaction ina child receiving sulfa therapy, the child should be evalusted, the sulfonamide Aiscontinued, and careful observaion begun ‘Trimethoprim plus Sulfamethoxazole (TMP-SMX) Trimedhoprim, available as a single agent, but used far more commonly in children in combination with sulfamethoxazole, acts at the metabolic step following that inhibited by sulfonamides in the synthesis of pirine bases." Ik prevents the formation of ‘eerahydofalie acid trom dihydrofolic acid by binding to and reversibly inhibiting. dihydrofolate reductase. The combination of sulfamethoxazole and trimethoprim blocks two consecutive steps in the synthesis of thymidine, providing both synergistic activity agains ‘most pathogens. and decreasing the risk of development of resistance to either the sulfa ageat or the trimethoprim. Trimethoprim displays ‘nactricidal setvity against bacteria, as does the combination, Sulfamethonazole a5 a single agent is not currently manufactured for tse in the United States. ‘Current clinical uses of TMP-SMX ate somewhat Finite in the treatment of UTI doe 1 increasing resistance of E. coll w this, combination, but TMP-SMX therapy is effective for regions of the ‘world in which susceptibility remains high and for children with a documented UTI in whom the susceptibility test results demonstrate susceptibility. The rate of pneumococcal resistance to alfa i mist areas ofthe United States is greater than 40%, precluding it as fist Tine therapy of acute otis media, sinusitis, or community-acguied Pneumonia. Despite in vio susceptibility of S. pyogenes to TMP- SMX, the use of this agent in the treatment of streptococcal ‘haryngits is not recommended due to failures in mirobiclgic ‘eaicaion ofthe ogansmn, Increasing use of TMP-SMX in the treatment of CA-MRSA. infections has occurred recently, although prospective, controlled studies were never performed for staphylococcal skin and skin Siructure infections prior 16 original antibiotic approval, o« since the emergence of CA-MRSA. In vitto Suscepsibility of CA-MRSA 10 "TMP-SMX is almost universal" TMP-SMX is also being used more frequently for hosptl- associated infections caused by some multidrug-tesstant enteric {gram-negative bacilli sich 39 Enterobacter and Klebsiella species and Stenormphamonas maltephilia (which remains susceptible). TMP. ‘SMX is generally not bactericidal for high-density inocula of gram- regative bacilli. Although prospective comparative studies ae not available, TMP-SMX is less tox than the polymy-xns (colistin, and may provide an adequate clinical response for infections in mest tissue sites, including meningitis, in situations for which no other well evaluated therapy options exis. Gastrointestinal infections caused by Salmonella and Shigella spp. and enteropathogenic stains of Escherichia coli were often weated With TMP-SMX in the past; however, the value of TMP-SMX has decreased as resistance in these gastebinestinal pathogens has increased." ‘The intracellular activity of TMP-SMX has. been Particularly advantageous in the weatment of susceptible stains of Salmonella, sven the intacellular locaton of the organisns during infection. Susceptibility of enteric pathogens should be assessed before TMP-SMX is selected for therapy. ‘Other specific, less common infections remain effectively teated with TMP-SMX. including brucellosis and nocardiosis. Prophylaxis and treatment of Pneumocystis cavini (P. jirvec!) pneumonia ih immunocompromised children (HIV-infected, or selected oncology Prtients) remain highly eTective, Sulfadiazine plus Pyrimethamine ‘This combination s setive ina numberof protozoan parasite disease, including toxoplasmosis and malaria. Clinical use in children is primarily limited to congenital toxoplasmosis. with treatment suring as soon as physiologic jaundice has resolved, and to older children have documented toxoplasmosis associated with immune cies (primarily HIV-related) Miscellaneous Nitrofurantoin Nitrofurantoin i unique antibiotic, characterized by a hydantoin rng with a nico-substitted furanyl side chain tht is metabolized within the bacteria to produce reactive compounds that are bactericidal. The mechanism of antibacterial activity is not well understood, but presumably oveurs by altering ribosomal proteins and ther important Intracellular structures. Both gram-positive. bacteria. Gneluding PART W Lstortory Dagnoss and Therapy of fectous DiseasesAoumicoia Agents cHAPTER 202 1447000) Soe toute Dasa per hen) comments “Amikacin Amin) no 15-225 mg divided ito 2-3 does = Seareey Vien eset tee Guinan Sate ee cae eee c 4 Peeters wim 15:25 ma dvd ini 2- es F ee iieriensde) Seoarth Gane ro 50-100 revel in 3-4 doses “Mini abd on lim fi cau 8 089) ewer mv 20-20 mg vied i 3 dows a 1-23) i VIM. ‘TR mg divided into 1-3 doses. Cystic fibrosis 7-10. mg. 1M ‘90-120 mg vided mt 4 doses [alt gs), masini Said) rar) (40-100 mg divide nto 4 doses (ada 14 way) mg divide ta 3 doves (ale 306 gy) 120m for meningitis Eupenem davanz) '30/mg dived ito 2 does, maximum tay ‘al | ds) Cephatsporinn’ Mathiciin-eitant sapiyossee fe esse fo all amen = ‘alla cephalosporins ‘Cofuroxl(Durce, Uae) Po ‘mp divide ito 2 doses a {au 1-2 gay, maximum 4 gf) Cefaclor (Cece) 0 “Amz divided inn 203 doses a (ool 15 play, maximum 4 e/a) wid Clason etl, Anco) 1M 0-100 mg divided ine 3 doses tat 5 6 gidayemaximam. 12 py) fixie (Supe) PO mg divided imo 1 or 2 dene adule 40 mgkiy) Poor antinaphylosocal activity (Cefoperarone(Cafobiy wi 100-150 mg divided ino 2 or 3 doses (at 2-4 gay, asia 12 ay) Ceforaxime (Clatoran) uM 50-180 me divided into 3 or 4 doses 200-300 mg divided int 4 doses “ual 36 gfday, rnin 12 gy) for meningitis (Cefoitin Metoxin) IM 180-160 mg divided ito 4-6 doses 2 ada 6 shy, esr 12 day) {Cefpadonime prot (Vania) PO 1) mg divided in 2 doses {ad 200-100 mglay, asin 800 men) (Cefprorl (Ceti PO 15-30 mg divided ino 2 doves (alt 05-1 pay, (ona, Tact Tze) Cefuten (Ged) Cefepime (Maxine) (Cefainis Once ‘Cefizoxime (Cetizox) rosin ty) NM 100-150 rg divided into 3 doses 200-30 fr serious {alt 34 sy, mar 6 ay) Prewomonas infection Po. 9 mg divided into 1 or 2 doses adul 400 may) 1M 100-150 mg divide nto 23 doses (adult 20 pay, anime 6 gia) fe PO 14 mg divide ino or 2 doses, maxi 600 mighty 150-200 ang iio ino 3 doses (adule 36 fy. maximum 12 9iy) Ceftriaxone (Rocerin) NIM 50-75 mz vie itn 1 oF doses 100 mg fr meningitis adale 12 fey, maximum 4 g/ay) ContinuedFs secrion Bv.ntcwo Merpy Dray Generic ade) Route Dosage per kay? Comments? Cefuroxime (inact) iM 100-240 mg divided into 3 doses adult 225-45 gay, Should ot be wsed if meningitis maximum 9 giday) ‘sponte Cefuroxime acti (Ceti) PO 30-40 me divided ito 2 03 doses, rmaxinm 1 Bay i Cephalexin Kefex) PO 25-50 mg divided io 4 doves (ade It gay) 100 mg fr esieoarcuar ‘Cephradine (Anspr, Velose) PO 725-50 ma divided ino 3-4 doves (al 4 pay) 100 mg for osteoarticular infestions| “Loracabet (Lari) 15-30 mg divided ito 2 doses adult 800 may) 0 mpg for AOM Pencils Peniilin Gand Vo PaniciliaG, eysaline Kor Na IM 100,000-250 00 units vided into 4-6 doses ‘Contains Naor Ky Adult &-26 million unity, axiom 1.68 mE, 000.00 unis Penicillin 6, procaine ™ 725,000-S0,000 units divided int 1-2 doses z {adult 60,000-12 sili units, ‘maximum 4.8 milion unity) Peis G, bevatine is) 50,000 units once (adult 12-24 ailion units once) (iilin LA) Ponicilin VK (oumerous) PO 25-50 mg divided into 3 or 4 doses 1600 ais = 1 mg optima ‘maximum 3 gay adult 5-2 gay, ‘istration on empty ‘maximum 72 gicay) Stomach ‘Peniclinase-resstant peniilins Medici ost staphylecoei e !ueresisan! tal penile Oxecilin (Bact NIM 150-200 me divided ita 4-6 doses 8 (ad 28 ayy asm 12 fay) [afeiin (Unipen, Naf) IM 100-200 mg divided into 46 dones e (dul 26 gay, manna 12 8a)) Dielorcillin Dynapen,Pathsil) PO 125-25 mg divided ino 4 doses 100 me for osenarcar (dul 05-2 giday, maxim 9) infetons Aminopeniciins ae it Ampiitin IM 100-200 mg divided into 4 doses 200-200 mide into des (alt $8 py, minimum 14 dy) Foc mening ‘Ampiilin-subacam (Unasyn) IV 100-200 mg anpleilin component cided ito doves (ult 48 gay) Ampéilinvampsilin hydrate PO 50 mg divided ito 4 doses (Principen) si al 1 ay, mani 1 gay) 2 Amoxicitia (Amoi) PO 40-100 mg divided int 2-3 doses Gait grasp ‘Amoxiciliaclavulaate PO. 141 formulation: 90 mg amoxicilia componeot ‘Tice dily dosing stds for ‘augmentin ‘vided into 2 dover cacy ony in AOM. 71 foemulaion. 25-45 me amoxieillin component divided ito? doses {41 formation” 20-40 mg amoxiiin component dived into'3 doses [Broad-spectrum penielins Catenin vO ‘30-50 mg divided into doses, maxim 3 fay Pperacilin wv 200-30 vide ina 3-4 doses © (odult 6-18 pay, maximum 24 eda) Piperacilincazobactam (Zasyn) WV 240 mg piperacilin component alive ito 4 doses (dul 12-18 hy) ‘iearinciavolaete v 200-300 mg dealin component divided Cte boss 300-600 me into 4-6 doses (adult 12-18 gay. maximum 24 gay) divided into 4 doses PART W Lebortry Dagnosis and Therapy cf InestousOseasesPe Onn ‘antimicrobial Agents Ce CHAPTER 292 Drug Generic (rade) out Dosage parka Comments! Chioramphenico™ W 50-75 mg divided ito 4 doses 75-100 mg for meningitis (Chloromyeetn) sadum-sucinate (adult maximum 4 si) -iuoroquinolones/Quinolones| “Anpath i potential ‘uoroqunolone class sid effet inchlien Nalin ae PO. 55 mg vida ito d doses (all 2-4 gay) 0 Nexfloxacia (Noroxin) PO 9-14 mg divided into 2 doses [aul 100-800 m/day, maximum 1.2 why) as Cipetiosicin Cipro) 0. "20-40 mg divided into 2 doves, mani 2 day Ww 20-20 mg divided into 2-3 doses, maximum 12 gay Ss Levofloracin (Levaquin) PO.1V 20 me divided ito 2 doses {ehidcen «5 yeas); 10 mg in needy dose {chen > 5 years) (ad 500-750 mgs) ‘ Ketolides ® z ‘Talitrorjn (Ketek) PO ‘Auli dose 800mg once dally “Lincosamides z Ctindamyia (Ceocin) mv 20-40 my divided into 3-4 doses {adalk 900 mg 2.7 sida. maximum 48 gay) Po 10-30mg divided ino 3-4 doses {adul 600m5g-18 gia. maximum 27 melts) - Lipopentides "a e F Dapromyein (Cubic) Ww ‘Adult done 4-6 mig once daily Fe Macrlides!Azalies ytvomyein (eumerous) Po. 20-40 mg divided into 2-4 doses ‘Available as base, stearate, yl (adult 1-2 pay, masimua 4 g/day) ccna, and estate reprationsand as rythvomyein-sulsoxazole v 20-40 mg vided into 4 doses (adult 1-2 say, nasi gay) Claritromyein (Biaxin) PO 15mg divides int 2 doves alt 5-1 play) : x ‘Azithromycin Zo) POV ‘Otis 10 mp per day outing dose on day then S mg/kg per da) days o 10 mpg perday #3 days; o 30 mere L Pharymits: 12 maf pec day 5 days Gasroeteris 10 mp per dy 3 days i Pewmona: 10 mghks per day 5 days 2 : “Mathenamine mandate PO 50-75 me divided into 2-4 doses (dulh2-4 fasy) For UT prophylaxis (Otandelamins) = = seo q Metroniente CFsg3)) PO. 15-35 me divided ito 3 doses W ‘30-40 mg divided into 3 doses (adult 1-2 pay, manu hy) ae = Niftofurantoin (Furadantn) PO 57 me divided into 4 doses (adalt 200-400 mid, 1-2 mgfkpsily for UTT swaximum 7 mek pe day) prophylaxis ee aos pied eo cee ne een Colistimethate(Cly-Myein M) YIM ‘5-7 mg divided into 3 doses Reserved for mulidrug-esisant ‘ran negative patiogens fecuse of neuro. and nephron Ww 15-225 mg divide ito 2-3 doses (adult dose same) Rifampin Riad) Rieximin Cxtaxan) PO 10-20 mg divide ito 1-2 doses (adlt 600-1200 mga) ‘Adult dose 00 mgiay divided int 3 doses[Miaso seerion B Au-ntecwve Mery Se) ‘rag Generic (race) out Dosage (pe kay" Commens* Sulfonamides Sliadarine PO 120-150 mg divided ino dons (alt 24 ay) Sulsoxaole(Gantisin) PO 120-150 mg divided ino domes Tinethondisoltanethoraole —1V,PO {312 mg TMP divided io 2 doses ada 160-320 mg 20-mg TMP evident 4 danse (EMP-SN0X) (Bari, Sepia) “TMPIdsy, maxinua 15 nig TMP per 3) oe Preumocyts cara preumena ‘ ‘etrayctines “Tecacyline lt abo sm "uerptod wet sei len 225 yeas of ae i bene exes ks “Tewacyline(oumeros) PO. 25-50 mg divided into 4 doses adult 1-2 gia) Minoeyline Minin) PO.1V 4g divided ito 1-2 doses adit 200 mg, ‘axiom 400 gin) Doyen numero) PO.1V 2-4 ng ives into 1-2 doses edu 100-200 mplisy) IV use asa 2-Hour inion “Tigeeyeline yeni) wv Adult dose 50mg wie daily ‘aneomgcin®(Vaneocin) wv 0 mig vided int 3 dones ‘Consider dose of 60 mf pay for meningitis Po 40 mg vided int doses Not aor fom Gl act (aul, 0 mg divided int 4 doses) Inavenricular 1-8 mg dy (al, 3-8 mg dah) ‘AON, ae ts madi GL. cist aes 1, ans, FO, oly UT, inayat non "Dose freien nd a the ub of dane un. kc) ps alas per dy sg ra svete marin dove hn, The oncogene {0 ess ar be crane aa de range opr er ayant ps) awe by hdl aan nf ow "Danes ne asa acting sem reno, “patent hry fre yey (epost ein cpio capes ot Be CE LA es ou eon < 204 eon» 208 chert tes fon reo! eee oben aie oe ee ee eg! ee Teal we fc SN com rte [Re a SCTE TS Ceforaxime VIM 100 div g 12 bours 190 div q 8 hours 100 div q I2hours 150 div gS hours | 150div q 8 hours: an (a Cran PART IV Laboratory Oignols ano Therapy of inectous saasosco Part 1 Table of Antibiotic Dosages for Neonat Antimiorobial Agents Anis ee ee ee Tie TRO | Waivg Hear aN atom [20d gthoa wav atten | wavg Sim lala TV | waa thew eaivg Shown | a0arg (tous 17 soa gious 7 | ooava 8h festeenks TAO | 73avq2shwan _(Saivq thew | avg (eas 30d Moun | 30a a6 han ‘etc cmin WW | sod iRtmin 7SuNaAna | 78dvasiow —_IGodvqsiown | Isda46boun Pekin G.tenatine Iw | =sQ0unin——s000unin——‘| saodunin——sooopann | SOD ats Sit aa oes aaa nee eres TeailaG cysatie Wn —aSoqune dv | HOMO wea 3000ED ts | BODO ani arthur eeu shorn oem a Tee TrasllnG.poaim ~~ ~SO00uiy——~S000unis—*YSAODunis—aPODeay | SOE ai gana yan vation gato | Sat Foenciimasoncan WV | 100dh'g Aims S0DdN 8a | 20Ddvg 2h” Og HinuD | AO g Shon Tila NRO | 10gMine 104M iw | 1042haws 042A | 10g 2owr Town NIM) 10du g1Bban 226d a8 aes | 224 divas man sndva Gham | MO dr «Show Ticarcillin-clavulanate IV [soi q 12 hous 225i q8hous | 225aivq Bows” 300 divq 6houn | 300div4 6 hours TN inven 1M, inane BO orl ‘Aalto doe for prs oa 10 hg ow ly for he eae Sd wetmen soe, here for oer infections, 10mg gen onthe at dy folio by Salt fet snes ls ile id ven 6 ugg pe yy gs far ta i 2 wet ie, ar which edness 100g ey v2 ous LS mg per ei eee eee ega 5K 252-2. Part Dosae (ne/O056 by Gaston Ag PLUS ns of te pais a 2 is sis >is faa Eiieeqiitiies i [a aSaitios Waitin? | 10asiea? Gentamicin” 2.5 q 24 hours! 2.5 q 18 hours’ 2.5.q 12 hours* [2 Sq 8 hours® Team wwist 23uMbant | a5qi8hows! | a5qiahowst | 25 qBhow? reat v [ais es 18g 2bom! | Saban! “Des serr cones: 2-0 jg, <10 gn (woh "Dest Serum cncnaton: $12 Ula, 20H ous ‘Doster concerti: 20s gah), 1018 usa och ‘Aker pin: £29 ie psn age OT dae Smt it 28 days, meee GIS: 220th th 30.3 wi: pom age O7 dys 4. gh 3087S dap cats oth ‘Once diy sng repten ania, 15 mo emancipate be ftv and nae, tne ropectvey ca er ae see a aie ee Staphylococci and streptococci) and gram-negative bacteria (E. coli Klebsiella. and Cirrobacter_ spp.) ate. susceptible. Mechanisms of resistance have not been wel defined, but no cross-resistance occurs to other antibiotic classes, Recent data from the United States on susceptibility of pediatric uropathogens document that, overall, resistance t0 nitrofurantoin across all pathogens and pediatric age groups is approximately Sto 10%¢."" Nitrofurantoin was originally FDA-approved in 1953 for the treatment of uncomplicated UTIs in adults and children 12 years of ‘age and older, Nitrofurantoin is well absorbed orally and is rapidly cleared from the serum, producing subtherapeutic concentrations in serum, but bactericidal concentrations in urine. Currently available formulations include ® rapidly absorbed monohydrate, salt, a monohydrate salt in slow-release matrix, and crystalline nitrofurantoin that is aso more slowly absorbed. Dosages should be decreased in children with any degree of renal insuffcieney, Inclinical practice this agent has been used for both treatment and long-term prophylaxis of UTI"! Current clinical use is primarily for prophylaxis, but few prospective comparative data are available fon Which to base these recommendations." Serious pulmonary toxicities, both aevte and chronic, were reported in the decade following availability of nitrofurantoin.! Acate lung injury, felt to cuarren 202 145100)[Es: section B Antec Theory be immune-mediated, and chronic fibrosis have been reported in ‘udulis daring long-term therapy. The rate and severity of these ‘multiple pulmonary toxicities have not been evaluated prospectively in children. However, no eports of pulmonary toxicity in young children receiving ntrofurantoin prophylaxis for UTI have been published in the past wo decades, despite continued widespread use. In addition to ppultonary toxicity, hemolysis secondary to glucose--phosphate Aehycrogenase deficiency has also been documented, Methenamine ‘Methenamine hippurate js used exclusively forthe prevention of UTI Initially aailable in 1967 and FDA-approved for patients down to 12 years of age, methenamine is a salt that ultimately exerts an antibacterial effect in the urine %s it becomes converted into Tormaldehyde. This effect occurs when the urine pl is below 5.5 Formaldehyde fas nonspecific bactericidal activity on both gram: positive and gram-negative bacteria, However, as the generation of formaldehyde is dependent on an acidic urinary pH, methenamine may not be active in situations in which a more aikaline pH is crested by diet, or by urea-spiting bacteria in the urine, such as Proteus and Pseudomonas. A recent review of previously published data on clinical tials of methenamine prophylaxis, some of which were published as early as 1966, was not dane ina prospective, randomized, blinded, fashion with well-defined endpoints." However, pooled analyses suggested a treatment benefit for prophylaxis of bacteriuria, although significant failure rate was still present in adults with acidified urine and documented adequate urinary formaldehyde foncenteaions." The clinical use of methenamine in children is limited. to sitwations in. which neither antimicrobial agents. nor intermittent catheterization techniques in children with urinary bladder voiding. dysfunction have been effective at_ preventing recurrent sympomatic UTIs, Microbiologie failures during methen- amine prophylaxis are nt uncommon, mmm 293 Antifungal Agents William J. Steinbach ani Christopher C. Dvorak Fungal pathogens are an increasingly recognized complication of forgan tcansplantation and the ever more potent chemotherapeutic regimens for childhood malignancies. For aver 40 years there has ‘been limited progress in the textment of invasive fongal infections and the field of pediatsic antifungal therapy has been largely ignored, ‘Although coaventional amphotericin B deoxycholate was the crue of ‘choice for many invasive fungal infections for years, newer, safer, and more effective agents have relegated it to antiquity. Lipid formulations fof amphotericin B have reduced the toxicity of conventional amphotericin B and these agents have a role in the management of several specific discases, such as zygomycosis and others. The newer triazoles, voriconazole and posaconazole, have expanded our options for therapy against mold infections such as invasive aspergillosis. The fechinocandins offer a new class of antifungal therapy swhere forthe first time there is no cross-reactivity with & human substrate, leading to minimal toxicities ‘There are now numerous nuances to choosing the correct anti- fungal drug, including the fungistaic versus fungicidal activity of certain anmifangal classes against various genera or even species of fungal pathogens. One of the most important aspects forthe successful management of invasive fungal infections in ehildren is the develop ment of a solid understanding of diferences in the pharmacokinetics fof these drugs in children and adults, which resales in more optimal Aosing ANTIFUNGAL AGENTS FOR TREATMENT OF SUPERFICIAL INFECTIONS Among the therapeutic options available for treatment of fungal infections of the har, skin, and nails, few have been tested in chikien, and fewer are approved Tor use in children younger than 13 years of age. Furthermore, extrapolating data from adults treated for dermato- ‘mycoses to infants and children may not be justified. For example Trichophyton tonsurans, although uncommon: in adults, is the most ‘common cause of tinea capitis and tinea corporis in children, ‘The use of topical agents should he confined to infections of the epidermis, hit, and nails. The choice of treating superficial fungal infections with'a topical ora systemic agent depends on the fungal pathogen, the ste of infection, and the extet of the lesion (see Chaper 255, Dermatophytes and Other Superficial Fungi), For example, @ systemic antifungal drug is almost always used for ringworm ofthe scalp, nails, palms, of soles; creams of solutions ate preferred foe {issured oF intertrisinous areas; and sprays are not recommended for the face. Over-the-Counter Preparations. Undoeylenic acid is an unsaturated fatty acid atifungal agent aval able as an ointment, powder, oF liguid. ls therapeutic efficacy was first recognized in the 19406 in treating superficial fungal diseases affecting military troops. However, undecylenic acid has litle efficacy ‘when compared with newer agents. Tolnaftate has similar activity against dermatophytes, with cure rates of 0% to 90%, but tinea pedis, tinea cruns, and tinea corporis resolve spontaneously in 20% t0 30% fof eases.’ Tinea capitis und tinea unguinum are frequently resistant, probably because of poor penetration of tolnaiate into involved areas. The advantages of these compounds are that they are safe, Inexpensive, and rarely eause local irritation Topical Polyenes Nystatin is polyene antifungal agent named after New York state. It ‘binds to ergosterol in the fungal cell membrane and causes changes in cell permeability and, eventualy, cel lysis. Nystatin is useful for the ‘weatment of ora, mucosal, and cutaneous infections caused by Candida. ti available asa suspension, powder, cream, oF ointment (100000 Uma. or Uig, respectively): pastile (200000 U) to be dissolved in dhe mouth an oral tablet (500 000 U); and a vaginal tablet (100000 U). Oral forms are administered four or more times daily and are well tolerated, although lange oral doses of the suspension can ‘cause nausea. Nystatin is not effective against the dermatophtes ‘Azoles Clotrimazole is an imidazole with broad-spectrum activity against Candids and the dermatophytes T. tonsurans, 7. rubrum, T. menta- _grophytes, Epidermophyton floccosurt and Mierosporuny canis (Table 293-1). This antifungal agent is also effective against Malaszeia uri, the cause of tinea versicolor. Clotimazole is one of the few Topical antifungal agents studied in children. The 1% eream, latin, and solution are avilable over the counter for the weatment of tine pedis, tinea eruris, and tinea corporis. High concentrations of cloti- azole are achieved topically, bt systemic absorption is negligible ‘Topical application is generally well tolerated but can cause local ination oF uniearia, Clotrimazole is also available with 0.05% beta methasone and appears to foster more rapid healing. in adults, However, this combination cream is not recommended for use it PART IV Lstortry Dagrois nd Therapy of fects Diseases