SURGERY Continues Langenbecks Archiv fur Chirurgie

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1 Lan enbeck's Arc ives f SURGERY Cntinues Langenbecks Archiv fur Chirurgie Organ f the Cngresses f the German Sciety fsurgery Editr-in-Chief Hans G. Beger, Ulm Editrs Christph E. Brelsch, Hamburg Bernd Kremer, Kiel Wilfried Lrenz, Marburg Knrad Mef3mer, Munich Friedrich-W. Schildberg, Munich Assistant Editrs Edmund Neugebauer, Clgne Michael H. Schenberg, Ulm Funding Editr Bernhard vn Langenbeck, Berlin Frmer Managing Editrs Werner Krte, Berlin Ferdinand Sauerbruch, Berlin Karl-H. Bauer, Heidelberg Fritz Linder, Heidelberg Martin Allgwer, Basel Michael Trede, Mannheim Springer Editrial Bard Hrst D. Becker, Tubingen Henri Bismuth, Villejuif Hans-P. Bruch, Lubeck Markus W. Buchler, Bern Gerhard Buef3, Tubingen Heinz J. Buhr, Berlin Jhn L. Camern, Baltimre Lutz Claes, Ulm Rbert E. Cndn, Milwaukee Valeri Di Carl, Milan Henning Dralle, Halle Albrecht Encke, Frankfurt Laurean Fernandez Cruz, Barcelna Abe Fingerhut, Pissy R. Jan A. Gris, Nijmegen Ulf Haglund, Uppsala Axel Haverich, Hannver Christian Herfarth, Heidelberg Yshiki Hiki, Kanagawa Ulrich T. Hpt, Rstck ngemar hse, Lund Clement W. mrie, Glasgw Karl-W. Jauch, Regensburg Hans Jeekel, Rtterdam The Junginger, Mainz Hlger Kalthff, Kiel Hans Lippert, Magdeburg Jacques Marescaux, Strasburg Keiichi Maruyama, Tky Michael D. Menger, Hmburg Enrique Mren Gnzales, Madrid Jhn P. Neptlems, Liverpl Peter Neuhaus, Berlin Brun Niederle, Vienna Juha Niinikski, Turku Yuji Nimura, Nagya Rland Pare, Paris Hward A. Reber, Ls Angeles Hans D. Rher, Dusseldrf Matthias Rthmund, Marburg Michael G. Sarr, Rchester Hans K. Schackert, Dresden Peter M. Schlag, Berlin Vlker SchumpeJick, Aachen Jrg R. Siewert, Munich Rnald K. Tmpkins, Ls Angeles Otmar Trentz, Zurich Hans Tridl, Clgne Andrew L. Warshaw, Bstn Samuel A. Wells, St. Luis Rbin C. N. Williamsn, Lndn Zhng Shu-xian, Beijing

2 Langenbeck's Arch Surg (1998) 383: Springer-Verlag 1998 REVEW TOPC: SEPSS D. H. Wittmann A. Wittmann-Tylr Scpe and limitatins f antimicrbial therapy f sepsis in surgery Received: 1 December 1997 Abstract Objective: The gal f antibitic therapy fr surgical sepsis is t kill bacteria that intermittently r cntinuusly reach the bldstream frm the residue f an peratively treated fcus. While sepsis and cnditins leading t sepsis cmprmise the immune system, antibitics may becme a fundamental determinant f the hst's defense. N data frm sund prspective randmized clinical antibitic trials deal ing with sepsis are avai lable. Therefre we tested the hypthesis that treatment recmmendatins can be based n pharmacdynamics cmparing in vitr activity f cmmnly used antimicrbials with cncentratins sustained in viv t prvide fr full cverage fr bacteria f cncern. Results: The applicatin f strict criteria fr antibitic chice t avid selectin f primary resistant strains reveals that mst cmmnly used antibitics render insufficient activity t eliminate pathgens that cmmnly cause surgical sepsis. Antibitics that sustain in viv cncentratin exceeding furfld the MC 1 (highest minimal inhibitry cncentratin fr all (1%) species tested) f Escherichia cli, fr example, are 4 mg ciprflxacin V (MC 1 f 1224 strains = mgdl, in viv cncentratin = mgdl fr 12 h), and 1 mg imipenemlcilastatin (MC JOO f 3142 strains =.14 mgdl, in viv cncentratin =2 mgdl fr 6 h). The third chice is ne f the furth- r, less cnvincingly, third-generatin cephalsprins. Similar data fr mst pathgens causing sepsis are prvided. First- and secnd-generatin cephalsprins and penicillin ~-actamase inhibitr cmbinatins generally d nt achieve sufficient cncentratins t cver the mst imprtant pathgens f sepsis. Cnclusin: Sepsis is defined as a whle bdy's inflammatry respnse that is characterized by systemic signs and symptms secndary t a fcal infectin. While many antibitic trials D. H. Wittmann (181) Department f Surgery, Medical Cllege f Wiscnsin, 92 West Wiscnsin Ave. FMLH West, Milwaukee, W 53226, USA A. Wittmann-Tylr Pennsylvania State University, Hershey, Pennsylvania, USA have dealt with a fcal infectin, n prspective randmized antibitic trial has dealt with sepsis per se. Antibitic trials n fcal infectins generally exclude patients when their fcal infectin has prgressed t sepsis. T circumvent the lack fcntrued clinical trials we shw that pharmacdynamics may prvide sund fundatin fr antibitic chice fr sepsis. Key wrds Sepsis Systemic inflammatry respnse syndrme Antibitics Pharmacdynamics Defense failure syndrme ntra-abdminal infectin nfected pancreatic necrsis Cntrlled clinical trial ntrductin Addressing antimicrbial therapy fr sepsis is a challenge because there is n clear agreement abut the definitin f sepsis, and the literature prvides n cnvincing therapeutic recmmendatins. Publicatins dealing in particular with antimicrbial therapy f sepsis are scarce, and the abundant literature dealing with antimicrbial therapy fr surgical infectin is nt very useful. Mst infrmatin is anecdtal; sme is editrial and intends t analyze the myriad f papers. Much f the experimental wrk n animal mdels translates insufficiently int current clinical practice. Finally, the results f many cntrlled clinical trials prmting the use f certain antimicrbials fr surgical infectins are incnsistent and incnclusive with regard t the ptimal chice. This great number f publicatins matches the cntinuing discvery f new antimicrbials by the pharmaceutical industry. The enrmus csts assciated with the develpment f new antimicrbials lead t marketing strategies that tend t misuse scientific publicatins t intrduce their biases, ften in a very subtle fashin. Fr the nnspecialist it is almst impssible t separate the wheat frm the chaff and t base therapy n sund research. Experienced surgens feel uncmfrtable with the tpic. On the ther hand, we are lucky t have a class f pharmaceu-

3 16 ticals at hand that is nt nly extremely effective when used crrectly, but that is assciated with very few adverse reactins. n this cntributin we rei terate current definitins dealing with surgical infectins and sepsis and use the infrmatin available t recmmend certain antimicrbials fr the treatment f sepsis riginating in a fcal infectin that may be surgically remved (surgical sepsis). We d nt reiterate perative principles f eliminating the fcus f infectin but assume that it is clear t the reader that successful treatment with any antibitic is impssible if the fcus is nt dealt with peratively. Materials and methds Definitins The fllwing definitins used in this paper are basel! n published infrmatin [1,19,2,65,961: Basic dejinirins Surgical infectin: any infectin that fllws cntaminatin f damaged tissue after perative r accidental trauma Alternatively, any infectin ccurring in a surgical patient after trauma r peratin at the surgical site r in remte rgans such as lungs and urinary tract. - Cntaminatin: clnizatin by bacteria f nrmally sterile tissue withut r befre evking any inflammatry respnse. - nfectin: an inflammatry hst respnse t invasin f bacteria int nrmally sterile tissue. - nflammatin: the hst's respnse t injury frm mechanical and chemical trauma, including trauma frm bacterial txins. t may stay lcalized in the area f tissue damage r spread beynd the lcal site and becme systemic. Definitins j systemic hst respnses - Sepsis: a whle-bdy inflammatin characteriz.ed by systemic signs and symptms. f the inflammatry reactin is verwhelming and is assciated with hypertensin, sepsis prgresses int septic shck. Bacteria mayr may nt be islated frm the bldstream, due t failure f taking bld cultures while the bacteria in the bldstream. - Surgical sepsis: sepsis riginating in a surgical fcus that may be eliminated by perative management. - Systemic inflammatry respnse syndrme: a systemic hst respnse similar t sepsis except that the triggers fr tissue injury are nt bacterial txins but massive tissue trauma such as mechanical injury r burns. - Defense failure syndrme: the set f cnditins bserved when sepsis r systemic intlammatry respnse leads t a dysfunctinal systemic immune respnse, while the rchestratin f humral and cellular immune factrs escapes cntrl (see Fig. 4). Useful bacterilgical pharmacdynamic definitins - Minimal inhibitry cncentratin (MC): the cncentratin required t kill 99% f a defined bacterial suspensin r culture, usually Hi' f clny-frming units per milliliter, within a predefined perid, usually h. - Time abve the MC: the time in which bacteristatic r bactericidal antimicrbial cncentratins are sustained in tissue where the infectin lies. Fr an antimicrbial therapy t be effective the cncentratin during the time abve the MrC must exceed fur times the MC required t kill a given micr-rganism. Prspective cntrlled trials Table cmpares mrtality rates in prspective antimicrbial trials [4,1,21,31,59,61,72,73,78,83,87,94] t thse in surgical series (64,91, 961 that d nt fcus n antibitic therapy. Antibitic cncentratins required t kill bacteria T btain representative infrmatin abut antibitic inhibitry and bactericidal cncentratins we cnsulted publicatins using similar methds apprved by the American Sciety fr Micrbilgy [1-3, 6,8,9,15-18,25-28,3,32-37,39,41-44,46,49,5,53-57,6, 63,67-69,74-77,81,81, A nt t recent perid f 3 years was cnsidered t exclude new resistance factrs that may nt be clinically relevant at this pint. The MC values f antibitics are measured in the labratry as killing either 9% (MC 9 ) r 1% (MC OU) f the bacteria. A MC 1 means that the MC f all pathgens tested is equal t r inferir t the reprted value. We reprt the MC 1 values t accunt fr the wrst-case scenari. Antibitics investigated include the secnd-, third-, and furth-generatin cephalsprins. the cabapenem imipenemcilastatin, aminpenicillins and extended spectrum penicillins, and penicillin~-actamaseinhibitr cmbinatins. Fr the quinlnes ciprflxacin has been used as an example. Antibitics nt listed in Table 21' 3 d nt prvide sufficiently high in viv cncentratins fr sufficiently lng perids t be tw t fur times abve the MrC JOO f pathgens fund in sepsis. Cncentratins achieved in viv fllwing V antibitics We selected three useful antibitics with different pharmackinetics fr the treatment f sepsis as examples t demnstrate in viv cncentratins and different pharmacdynamics. The cncentratin changes ver time fr bth central and glbal peripheral cmpartments are depicted n an expnential scale. Fr better appreciatin f cncentratins sustained in infected tissue an additinal timecncentratin curve is drawn n a linear scale. We used ur wn data frm earlier studies [19,88,92,93]. Results Results f antibitic trials and surgical series Table 1 cmpares results f selected cntrlled trials with thse surgical series using intra-abdminal infectin as an Table 1 Reference Mrtality in antimicrbial trials and in surgical series Antibitic trials Vestweber et al (78] Strm et al (731 Willmann et al (94]" 'Brien et al [59J Andrulakis et al. [988 [4] Birn et al. 1989[11 Eklund et al [31] Plket al [61) Walker et al j Slmkin et al [72) Cndn et al [21) Wilsn 1997 (87] Nnantibitic trials Schein et al [65, 96] Willmann et al (64) a N exclusins Mrtality (%) 4. 5A

4 17 Table 2 Maximally pssible inhibitry cncentratins (MC l ) fr selected gram-negative pathgens frm cllected data f representative studies; bacteria listed here have a MC less than the in viv cncentratin f the listed antibitics fllwing intravenus administratin Table 3 Maximally pssible inhibitry cncentratins (MC l ) fr selected bligate anaerbic pathgens frm cllected data f representative studies; bacteria listed here have a MC Jess than the in viv cncentratin f the listed antibitics fllwing intravenus administratin Bacterium Antibitics Number f strains tested MC 9 MC 1 (mgdl) (mgdl) Bacterium Antibitics Number f strains tested MC 9 (mgdl) MC OO (mgdl) Acinetbacter anitrafus Acinetbacrer sp. Aermnas hydrphilia Aermnas sp. Citrbacter diversus Citrbacter freundii Escherichia cli Enterbacter aergenes Enterbacter agglrnerans Enterbacter clacae Enterbacter sp. KLebsiella xytca KLebsiella pneumniae KLebsiella sp. MrganeLLa mrganii Neisseria gnrrhea Prfeus mirabilis Prteus vulgaris (indle ps.) Prvidencia reltgeri Prvidencia stuartii Sen-alia Liquefaciens Shigella sp. Crynebacterium JK grup mipenem Ci prflxacin mipeem Ciprflxaci Cefpirme Ceftaxime mipenem mipenem Cefpirme Ciprflxaci Cefpirme mipenem Cefpirme Ceftaxime Ceftaxime CiprfJxacin Ceftaxime Ceftaxime Cefpirme mipenem CiprfJxacin Cefpirme Ceftaxime Cefpirme Ceftaxime CiprfJxaci n OA OA Anaerbi ccci Bacterides melaningenicus Bacterides fragilis Bacterides sp. CLstridium difficile Clstridium pelfringens Fusbacterium sp. Peptpsfreptccci n viv cncentratins Examples f antibitic cncentratins that are sustained in bld and tissue fllwing the administratin fhigh dses are shwn in Figs. 1-3 fr ceftriaxne, imipenemcilastatin, and ci prflxacin. Cncentratins that are sustained fr a certain time are clearly visible n the linear (b) graphs. Cmparing in viv cncentratins with the MC 1 prvides a time that crrespnds t that abve the MC. The infrmatin applies t all pathgens f a species and includes all resistance ptential as well. Fr example, if ne decides t treat E. cli sepsis with looo mg imipenem cilastatin every 6-8 h V, all strains are likely t be cvered, including all pssible resistant strains (see als Tables 2, 3). n vitr cncentratins (MC) Tables 2 and 3 list MC levels belw cncentratins that may realistically be achieved in viv fllwing intravenus administratin f tested antibitics. The data represent the mean MC 9 and MC 1 f many strains tested in independent publicatins. Only data n bacteria with an MC lo at least tw times belw realizable in viv cncentratins are included. Discussin mipenem 5 mipenem 9 Metrnidazle 921 mipenem 92 J56 Cefpirme mipenem 95 Metrnidazle Metrnidazle 69 mipenem 1 Metrnidazle <O.OJ <.1 2A.5 A 3.6 OA <.1 O.LO < example. Mrtality f intra-abdminal infectin in surgical series is seen here t be 3% and thus many times higher than that reprted in antibitic trials, which is 4.6% fr the same cnditin. The definitins f surgical infectin and sepsis have changed many times. As early as 1911 Schttmi.iller defined sepsis as a systemic reactin t the invasin f bacteria int the bldstream [66]. He nted that, "Sepsis is

5 18 Fig. la, b Parmackinetics f 2 mg ceftriaxne. a Serum and tissue cncentratins fllwing administratin f 2 mg ceftriaxne V blus. Nte the prtracted filling f the peripheral cmpartment "tissue," which is related t the high binding rati (9-94%) f ceftriaxne t serum prteins. Fr nnexpnentiaj display f tissue cncentratins see Table. b Tissue cncentratin f ceflriaxne (2 mg V) :::J "C C!. l: :;:; E-l: Q) (J l: U _-----_._._ _._-----_._ _._--, -.' ~ a Time in Hurs E 26 ~ Z «~ Z W 14 U 12 Z 1 U b Cncentratin sustained fr 24 hurs TME (HOURS) - present when pathgenic bacteria prceed peridically r cnstantly frm an infectius fcus int central circulatin in a way that this invasin evkes an bjective hst respnse resulting in subjective symptms." n subsequent years, hwever, authrs have ften used the term sepsis t dente lcal rather than systemic events (e.g.,"wund sepsis") and have increasingly blamed exclusively bacteria and their txins fr the deleterius events f septic shck. Meanwhile they have lst sight f the hst respnse as the majr culprit. This errneus understanding still prevails in updated medical dictinaries. n the late 197s the absence f infective fci in patients with intra-abdminal infectin and "dying a septic death" led t the evlutin f the cncept f "sepsis withut infectin" [38,4]. Meakins et a!' [52] termed this phenmenn "nn-bacteriemic clinical sepsis." Others have named it "sepsis withut bacteria" [51], "hypermetablic rgan failure cmplex," and the "systemic septic respnse [14]." When prgressing t uncntrlled systematic inflammatin, the term "defense failure syndrme" llay better describe the scenari that we cannt yet successfully treat (Fig. 4) [96]. These bservatins interfered with the ntin that sepsis, as infectin, requires the presence f bacteria. With the realizatin that the septic disease state is assciated mre with systemic hst respnse than with bacteria per se, the terms "sepsis" and "infectin" culd n lnger be used interchangeably. Schttmiiller's [] riginal cncept, which had been frgtten, nw needed t be rediscvered. A cnsensus cnference has develped a "new" set f definitins, which define infectin as the lcal hst's respnse t the invasin f micr-rganisms, and sepsis as

6 Fig. 2a, b Pharmackinetics f 1 mg imipenem. a Serum and tissue cncentratins fllwing shrr infusin f 1 mg imipenemcilastatin in patients aged ver 5 years. Fr nnexpnential display f tissue cncentratins see Table 2. b Tissue cncentratin fllwing 1 mg imipenem :::J "C C,.s r:: ~ ~ 'E Cl g u 1., , , -Serum --Tissue 1. -1J ~2_...::_ a Time in Hurs :::J 18 "C c C! 16 E. 14 l:: 12 :;:; 1l 1...-l:: 8 Bl:: 6 <.> 4 2 b ~ '" '" '".~ "" ""-. Cncentratin sustained fr 6 hurs ~ ~ 1 i i i Time (Hurs) the systemic respnse f the hst t the same challenge [13]. The massive hst respnse seen after a nninfectius trigger such as massive trauma r burn is referred t as "sepsis syndrme" because f its similar hyperdynamic hemdynamics and immune respnse pattern. This later became a distinct entity knwn as systemic inflammatry respnse syndrme [12]. What is special abut surgical infectin and sepsis? Surgical infectins and sepsis related t surgical infectins differ frm sepsis assciated with nnsurgical infectins. Unlike nnsurgical types f sepsis, such as thse riginating frm pneumnia r urinary tract infectins in surgical infectins, there is an infectius fcus amenable t perative management. Operative management aims at either eliminating the infectius fcus r reducing the bacteria inculum t sizes that can be treated successfully with antimicrbial therapy. Antimicrbials are much mre likely t eliminate remaining bacteria nce the appendix is remved, the cln perfratin is clsed, and bacteria are purged frm the abdminal cavity. n this instance shrt curses f prper antimicrbials suffice t eliminate thse bacteria that have prgressed int adjacent and distant tissue. On the ther hand, it may be extremely difficult t remve the fcus peratively in, fr example, infected pancreatic necrsis, and lnger perids f antibitic therapy are required. Mrtal)ty f sepsis Sepsis remains a ptentially lethal prblem f cncern. There is a need t better understand its pathphysilgy, t cntrl deranged hemdynamics and metablism, and

7 2 Fig. 3a, b Pharmackinetics f 4 mg ciprflxacin. a Serum and tissue cncentratin f 4 mg ciprflxacin V. Nte excellent penetratin f drug int the tissue cmpartment. See als display f peripheral cmpartment cncentratins n a linear scale in b. b Tissue cncentratins f 4 mg ciprfixacin :J' "C-t» E c: ::: nl... c: G.l C) c: () a Time in Hurs ::r "' OJ 4.,S c: 3. :;; l'tl c: G.l (,) c: U 1. Cncentratin f 1 mgldl sustained fr 12 hurs 1- -Tissuel b Time in Hurs SRS - Cmplex Systemic nflammatry ReSp'llse Syndrme frm 'Any Cause Systemic nnammatin fl"m nfectin rstemlc nflammatin frm"trauma r ]3l:lrn Defense Failure Syndrl1.!e Fig.4 Systemic inflammatry respnse syndrme (SRS) cmplex. Defense failure syndrme may be a gd term t describe a disease state in which sepsis r SRS prgresses t irreversible systemic inflammatin t better treat the cnditin with nnantimicrbial, biengineered medicatin [7]. The prblem f sepsis, hwever, may have been highly exaggerated in recent reprts [5]. The ften-cited data that sepsis afflicts mre than 4, patients and accunts fr $5-1 billin f health care expenditures in the United States annually [5] require careful interpretatin. Many terminal patients develp sepsis while dying frm their underlying cnditin. Preterminally they ften develp signs f sepsis, a fact that is nted in the death certificates and then enters statistics. Recent Eurpean studies reprt that 9% f nncardiac intensive care admissins have clinically suspected and later cnfirmed severe sepsis [61]. Within 28 clays f admissin 56% f thse with psitive bld cultures and 6% f thse with negative cultures die. These clata may be representative, and a challenge fr therapeutic imprvements. They als underscre the inadequacy f current antibitic therapy.

8 21 N direct infrmatin is available abut mrtality frm sepsis assciated with surgical infectin. T help estimate the prblem ne may lk at sepsis frm intra-abdminal infectins r secndary peritnitis. n cllected surgical series mrtality rates range between 15% and 3% [91, 96]. n interpreting this infrmatin, hwever, ne must cnsider that mrtality depends n risk factrs, and that nt all patients with intra-abdminal infectins develp sepsis. True sepsis cases prbably have higher mrtality rates. Limitatins f antibitic therapy f sepsis There are three majr reasns fr therapeutic failures in treating sepsis: (a) when therapy is initiated t late, and the patient's physilgy has already irreversibly deterirated; (b) when perative cntrl f the infectius fcus is nt pssible; and (c) when antibitics fail. The crrect chice f antibitic, dse, and timing can ptimize antibitic therapy and reasnably reduce antibitic failures. The antibitic t treat sepsis must be chsen withut the benefit f prperly cnducted cntrlled prspective trials because such studies prvide n infrmatin [65, 71]. Mrtality in antibitic trials is lwer than in surgical series where the antibitics have nt been the fcus, as shwn in Table 1. Antibitic trials that are generally funded by invlved industry tend t exclude patients with high risk fr negative utcme. The subset f exclusins therefre invlves the sickest f all patients, particularly thse with sepsis r pending septic shck. This fact was first nted by Slmkin et al. [71] wh bserved a mrtality f n mre than 3.5% in antibitic trials fr intra-abdminal infectin while that in surgical series is generally ver 25%. Recently this has been recnfirmed in a cnsensus statement [65] (see Table ). Mrever, n study is available dealing exclusively with the subset f patients whse surgical infectin has prgressed t sepsis and septic shck. Cnsequently t answer the questin abut ptimal antibitic treatment fr sepsis we cannt rely n hard cl inical data and must instead use the infrmatin f basic science at hand. There is sund scientific infrmatin abut cncentratins required t kill bacteria in vitr (Tables 2, 3). We als have a fair understanding f hw much antibitic cncentrates in the patient's tissue and bld fllwing intravenus injectin (see examples in Figs. 1-3). Cmparing the latter tw may therefre prvide a better predictr f clinical efficacy than the flawed antibitic trials [65,71,9]. The data in Tables 2 and 3 shw a wide range f bacteria that may be islated in septic patients. They als shw selected antibitics that are mst likely t kill sepsis pathgens when administered intravenusly at the dses indicated. n ther wrds, the MC f the pathgen is several times less than the in viv cncentratin fr sufficiently lng perids. The antibitics selected may be representative fr their classes fcurrently used, mst acti ve antimicrbials. Many f the ther cmmnly used antibitics have M1C values far greater than the critical in viv cncentratins and are therefre nt listed. Althugh penicillin ~-lactamaseinhibitr cmbinatins have been strngly prmted by the pharmaceutical industry, in mst cases the cncentratins required t kill pathgens f sepsis are far in excess f the cncentratins that can be achieved in tissue. The values fr MC l are utilized because patients with sepsis are severely immune cmprmised, and ne shuld chse nly an antibitic that fully cvers 1% f the ptential pathgens. The data presented here cver the inherent resistance f bacteria that may develp and becme an issue fr every patient in every hspital dealing with sepsis. T be n the safe side, it is imprtant t extend cverage t pssible resistant micr-rganisms. Such ptential fr resistance is usually bserved in the labratry lng befre it is bserved in patients. Due cnsideratin f resistance ptential is therefre an integral element f ur recmmendatins in Tables 2 and 3. T supprt the ntin that 1% cverage is meani ngful, ne may want t lk at the activity f simple penicillin G n grup A streptccci. n spite f its extensive use during the past 5 years, grup A streptccci has nt becme resistant. n viv penicillin cncentratins far exceed the bactericidal cncentratins sustained in viv, even with lw dses f the antibitic. Even tday penicillin remains the first chice fr grup A streptcccal sepsis. Scpe and treatment recmmendatins The gal f antibitic therapy fr sepsis is t kill bacteria that intermittently r cntinuusly reach the bldstream frm the residue f an peratively treated fcus. The dse must be high t achieve in viv cncentratins at least furfld the bacterial MC [22]. Since sepsis and cnditins leading t sepsis cmprmise the immune system, the hst's defense may be f little help in eliminating invading and multiplying bacteria. Antibitics may remain the sle defense. f nt all pathgens are fully cvered, primarily resistant strains may becme a clinical prblem after initial antibitic success. T circumvent such selectin f resistant strains strict criteria fr antibitic chice are prvided in Tables 2 and 3. The first chices fr antibitics are thse that sustain in viv cncentratin mre than furfld in excess f the MC 1' Fr E. cli sepsis, fr example (Table 2), the first chice is 4 mg ciprflxacin V (MC = mgdl, in viv cncentratin = mgdl) r a similar quinlnes. The secnd chice is 1 mg imipenemcilastatin (MC 1 =.14 mgdl, in viv cncentratin = 2 mgdl), and the third is ne f the furth-generatin cephalsprins. With respect t the third-generatin cephalsprins nly ceftaxime is listed because substances such as cefmenxine, ceftizxime, and ceftriaxne have very similar activity and may be substituted. f n antibitic is available fr a specific rganism, ne needs t cmprmise and chse a substance that cncentrates less than furfld the MC 1' Als, a large difference between MC 9 and MC OO may indicate that nly a few rganisms are nt cvered. n this case ne may take the risk f chsing the antibitic and relying n sme remaining bst defense t eliminate the resistant bacteria. Whether the presence f persistrs amng bacterial cl-

9 22 Table 4 Maximally pssible inhibitry cncentratins (MC 1) fr selected gram-psitive pathgens frm cllected data f representative studies; bacteria listed here have a MC less than the in viv cncentratin f the listed antibitics fllwing intravenus administratin Bacterium Antibitics Num- MC go MC l ber f (mgdl) (mgdl) strains tested StaphyLcccus aureus, Ceftaxime xacillin sensitive StaphyLcccus aureus mipenem Cefazlin Staphylcccus aureus, Cefazlin methicillin sensitive StaphyLcccus Cefurxime epidermidis StaphyLcccus Cefazlin epidermidis, methicillin sensitive Streptcccus agalactiae mipenem (grup B) Ceftaxime 28.1 Cefurxime Cefazlin Streptcccus Ceftaxime pneumniae mipenem Cefpirme Ceftaxime 2 Ampicillin Sulbactam Cefurxime Streptcccus pygenes Penicillin G (grup A) Cefpirme Ceftaxime mipenem Cefazlin Cefurxime nies that survive in spite f being fully sensitive t the antibitic plays a rle in sepsis is nt knwn [45,58]. Sepsis due t plymicrbial infectius fci Since surgical infectins are mre likely t be plymicrbial, it may be difficult t identify the pathgenic rganism that causes sepsis. The bacterial spectrum f intra-abdminal infectins, fr example, as listed in Table 4, shws that it is impssible t cver all ptential pathgens fr the disease [48]. The chice f antibitics must therefre cver the mst cmmn and mst pathgenic rganism f this spectrum [89]. n intra-abdminal infectins, hwever, target bacteria fr treatment have nt changed ver the years. Endtxin-prducing E. cli is still target number ne, utnumbering ther pathgens in islatin frequency and pathgenicity. Entercccus is the ther extreme and is nt knwn t prduce txins that can cause sepsis. Due t tremendus selectin pressure in mdern leu settings, bacteria that classically cause endtxic shck (septic shck) are replaced by numerus secndary pathgens (see Tables 2, 3). Table 5 Micr-rganisms islated in 255 intra-abdminal infectins befre administratin f antimicrbial therapy (all islated frm patients enrlled in prspective cntrlled randmized antibitic trials) slates Gram-negative bligate anaerbes 398 Bacterides 35 Prphyrmnas 18 PrevteLla 27 Fusbacterium 48 Enterbacteriaceae 231 Escherichia cli 14 Klebsiella 33 Enterbacter 19 Prteus 15 MrganeLl mrganii 3 Prvidencia alcilifaciens Citrbacter 12 Kluyvera ascrbata 2 KsereLLa trabulsii 3 Cedecea Lapagei Yesrsenia entercica 2 Pseudmnas 33 Gram-psitive facultative and bligate anaerbes 427 StaphyLcccus 34 Entercccus 7 Streptcccus 184 CLstridium 35 Peptstreptcccus 78 GemeLla 26 Prspects The dilemma f being unable t base antibitic recmmendatins fr sepsis n the results f sund, prspective, randmized clinical trials may encurage researchers t perfrm such trials withut selectin bias fr patients. Risk stratificatin may be ne way ut f excluding the sickest patients [7,72]. Sepsis per se may be difficult t study independently frm the underlying surgical infectin. nstead, it may be sufficient t identify a subset f patients with sepsis in studies dealing with a defined infectin such as an intra-abdminal infectin r infected pancreatic necrsis and t analyze sepsis patients separately. Duratin f antibitic therapy The duratin f antibitic administratin is generally t lng [9]. A recent expert frum discussed the issue and prduced recmmendatins fr shrtening the duratin f antimicrbial therapy [65]. n cases f sepsis antimicrbial therapy shuld cntinue as lng as there is evidence f live bacteria. Differentiating between infectin and nging inflammatry respnse withut any surviving bacteria in tissue, hwever, may be extremely difficult, and the duratin may depend n the surgen's judgment f hw well he was able t eliminate the fcus f infectin. n

10 23 Steady-state versus shrt infusin ntermittent chemtherapy is currently the standard in antibitic therapy. Mdern technlgy may make it pssible t achieve steady-state cncentratins in the patient by cntinuus infusin. t has been shwn that cntinuus infusin is at least as effective as the intermittent applicatin f antimicrbials [23, 24, 29, 47, 82]. Dynamic antibitic switching Further investigatin is required regarding dynamic antibitic switching [95]. Since n single antibitic can eliminate all bacteria f a plymicrbial surgical infectin, ne may assume that each antibitic can eliminate the sensitive bacteria in a few days. Switching frm ne antibitic t anther substance r cmbinatin that cvers the gap f the first antibitic may then cver remaining resistant bacteria. After 2 days a number f resistant bacteria will remain, and a third regimen shuld be initiated t cver the remaining gap. References. Aasen AO (199) Surgical pathphysilgy. 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