Antibiotic Induced Sepsis

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Antibiotic-induced Antibiotic-induced SepsisSepsis

Amr Badreldin Hamdy MD FCCPAmr Badreldin Hamdy MD FCCP

04/12/2304/12/23 amr badreldin hamdy MD FCCPamr badreldin hamdy MD FCCP 22

ObjectiveObjective

Define Define sepsissepsis and antibiotic and antibiotic induced sepsis.induced sepsis.

Highlight possible Highlight possible mechanismsmechanisms of antibiotic induced sepsis.of antibiotic induced sepsis.

How toHow to avoid avoid the condition. the condition.

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SepsisSepsis originally meant originally meant putrefactionputrefaction, a decomposition , a decomposition of organic matter by bacteria of organic matter by bacteria and fungi.and fungi.

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SepsisSepsis has now come to has now come to be recognized as the be recognized as the systemic systemic response to infectionresponse to infection..

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In In sepsissepsis there is an there is an exaggeratedexaggerated stimulation of the stimulation of the normalnormal host responses to the host responses to the invading pathogen, leading to a invading pathogen, leading to a widespread releasewidespread release of of inflammatory mediatorsinflammatory mediators and and vasodilatation.vasodilatation.

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SepsisSepsis is defined as a is defined as a condition with condition with feverfever, , tachycardiatachycardia, , tachypneatachypnea and and leukocytosisleukocytosis or or leukopenialeukopenia caused by infection.caused by infection.

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SepsisSepsis is severe inflammatory is severe inflammatory response syndrome response syndrome (SIRS)(SIRS) with with a a presumedpresumed or or confirmed confirmed infectious process.infectious process.

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Severe sepsisSevere sepsis is sepsis with is sepsis with signs signs ofof at least at least one acute organ one acute organ dysfunction:dysfunction:

Respiratory Respiratory

CVSCVS

Renal and hepaticRenal and hepatic

HematologicHematologic

CNSCNS

Unexplained metabolic acidosis.Unexplained metabolic acidosis.

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When When hypotensionhypotension persists persists despitedespite adequate fluid adequate fluid resuscitation and hypo-perfusion resuscitation and hypo-perfusion or organ dysfunction is present or organ dysfunction is present the term the term septic shockseptic shock is used. is used.

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The term The term SIRSSIRS describes describes patients who exhibit a patients who exhibit a sepsis-sepsis-like syndromelike syndrome, but who are, but who are not not infectedinfected. It may be precipitated . It may be precipitated by by insultsinsults such as such as pancreatitispancreatitis, , burnsburns or or traumatrauma, in addition to , in addition to many conditions which are less many conditions which are less common.common.

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Circulating Circulating endotoxinendotoxin can can induce an overwhelming induce an overwhelming inflammatory host response inflammatory host response (=(=systemic inflammatorysystemic inflammatory responseresponse or or sepsis cascadesepsis cascade))

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EndotoxinEndotoxin stimulates stimulates reactions such as the release of reactions such as the release of cytokines cytokines and and arachidonic acidarachidonic acid fromfrom monocytes monocytes , , neutrophils,neutrophils, and and vascular endothelial cellsvascular endothelial cells..

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A number of in vitro and in A number of in vitro and in vivo studies have shown an vivo studies have shown an increase in increase in endotoxinendotoxin release release after exposure to antibiotics.after exposure to antibiotics.

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In patients with In patients with uncomplicateduncomplicated gram –ve infections, antibiotic-gram –ve infections, antibiotic-inducedinduced endotoxin endotoxin release is release is most probably of limited value.most probably of limited value.

In patients with In patients with progressing progressing severe sepsissevere sepsis or who have or who have developed developed septic shockseptic shock, an , an additional dose of additional dose of endotoxinendotoxin may be deleterious.may be deleterious.

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EndotoxinEndotoxin has been associated has been associated with a with a myriad of diseases and myriad of diseases and syndromes:syndromes: complications complications associated withassociated with traumatrauma, , burnsburns and and invasive surgeryinvasive surgery, as well as organ-, as well as organ-specific illnesses such as specific illnesses such as cystic cystic fibrosis, inflammatory bowel fibrosis, inflammatory bowel disease, liver disease, kidney disease, liver disease, kidney dialysis complications, asthma and dialysis complications, asthma and autoimmune diseases.autoimmune diseases.

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Gram-ve bacteriaGram-ve bacteria all contain all contain LPSLPS as their as their major pathogenicmajor pathogenic determinant.determinant.

Gram+ve bacteriaGram+ve bacteria contain a contain a number of immunogenic cell number of immunogenic cell wall components besides the wall components besides the highly deleterious highly deleterious exotoxinsexotoxins..

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LipopolysacharidesLipopolysacharides play a play a pivotal role in the pivotal role in the pathomechanismpathomechanism of of sepsis.sepsis.

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BacteriaBacteria are the are the most most common agentscommon agents causing causing septicseptic shockshock but but fungi, mainly , mainly candida albicanscandida albicans, as well as , as well as parasitesparasites and and virusesviruses may be may be responsible in rare cases.responsible in rare cases.

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It is well known that bacterial It is well known that bacterial products, like products, like endotoxinendotoxin from from the gm-ve and the gm-ve and exotoxinsexotoxins from from the gm+ve bacteria, in different the gm+ve bacteria, in different ways ways initiate initiate the the inflammatory inflammatory host response in sepsis and that host response in sepsis and that this may further this may further progressprogress to to severe sepsissevere sepsis and and septic shockseptic shock..

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Among bacterial agents Among bacterial agents E.coliE.coli, , group beta streptococcigroup beta streptococci and and ListeriaListeria predominate in the predominate in the neonatesneonates, whereas , whereas pneumococcipneumococci, , meningococcimeningococci and and S.aureusS.aureus are the most are the most common causative agents in common causative agents in childrenchildren and and young adultsyoung adults..

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Since the 1980s there has Since the 1980s there has been a been a resurgenceresurgence of severe of severe group Agroup A streptococcalstreptococcal infections infections with rapid progression to toxic with rapid progression to toxic shock in patients of shock in patients of all agesall ages, , also including otherwise healthy also including otherwise healthy young persons.young persons.

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Septic shockSeptic shock in in elderlyelderly patientspatients is more frequently is more frequently caused by caused by gm-ve bacteriagm-ve bacteria from from the the gastrointestinal,gastrointestinal, urinaryurinary and and respiratory tractsrespiratory tracts..

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The term The term endotoxinendotoxin refers to refers to biological activitybiological activity of the of the lipopolysacharide molecule lipopolysacharide molecule ((LPSLPS) in the cell wall of the ) in the cell wall of the gramgram negative bacterianegative bacteria..

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EndotoxinsEndotoxins are are complex LPScomplex LPS, , major major cell wall componentscell wall components in all in all gm-ve bacteria. gm-ve bacteria. LipopolysaccharideLipopolysaccharide has two has two regions: regions: polysaccharidepolysaccharide and and lipid Alipid A..

Lipid ALipid A, highly conserved , highly conserved across bacterial families, is the across bacterial families, is the primary toxicprimary toxic component. component.

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Once in the circulation, the Once in the circulation, the lipid Alipid A moiety of moiety of endotoxin endotoxin prompts the release of prompts the release of endogenous mediatorsendogenous mediators such as such as TNF@,TNF@, IL-1IL-1, , IL-6IL-6 and and other other cytokines.cytokines.

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EndotoxinEndotoxin release from the release from the bacterial wall bacterial wall occurs mainlyoccurs mainly as a as a consequence of consequence of deathdeath and and lysis lysis of of the cellthe cell and of and of growthgrowth by cell by cell divisiondivision. When the . When the endotoxinendotoxin is is released and appears as released and appears as free free endotoxinendotoxin, its biological activity , its biological activity increases considerably as increases considerably as compared with the bacterialcompared with the bacterial cell- cell-boundbound endotoxin.endotoxin.

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Once released, Once released, endotoxinendotoxin binds to several binds to several receptorsreceptors and and carrier proteinscarrier proteins, the most , the most important being the important being the LPS LPS bindingbinding protein (LBS).protein (LBS).

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Gram+ve bacteriaGram+ve bacteria like like staphylococcistaphylococci and and streptococci streptococci produce produce exotoxinsexotoxins with varying with varying biological activities that can be biological activities that can be released without bacterial released without bacterial growth or lysis.growth or lysis.

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In similarity to In similarity to endotoxinendotoxin, the , the exotoxins exotoxins stimulatestimulate monocytes monocytes andand macrophages macrophages to release to release TNFTNF and other and other cytokinescytokines. In addition, . In addition, they have they have super antigenicsuper antigenic properties, meaning that they are properties, meaning that they are mitogenicmitogenic for certain T-cell subsets for certain T-cell subsets but do not require processing by but do not require processing by antigen presenting cells.antigen presenting cells.

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The release of The release of exotoxinsexotoxins, , many of which are many of which are superantigenssuperantigens, by gm+ve , by gm+ve bacteria bacteria activates T-cellsactivates T-cells, , resulting in a different cellular resulting in a different cellular response and different cytokine response and different cytokine profile, with relatively low levels profile, with relatively low levels of TNF@, IL-1, and IL-6 and of TNF@, IL-1, and IL-6 and increased levels of increased levels of IL-8IL-8..

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In general, In general, bactericidalbactericidal antibiotics antibiotics liberate initially moreliberate initially more endotoxinendotoxin than than bacteriostaticbacteriostatic antibiotics, and antibiotics antibiotics, and antibiotics active active on the cell wallon the cell wall, such as , such as penicillinspenicillins and and cephalosporinscephalosporins, , release morerelease more endotoxn endotoxn than than antibiotics with other modes of antibiotics with other modes of action, such as action, such as protein synthesis protein synthesis inhibitorsinhibitors..

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Penicillin-binding proteinsPenicillin-binding proteins (PBP(PBP) ) are are enzymesenzymes that are located in the that are located in the bacterial cell wall and bacterial cell wall and responsible responsible for the cell wallfor the cell wall synthesissynthesis. They are . They are also the also the primary targetsprimary targets for the beta- for the beta-lactam antibiotics and, depending lactam antibiotics and, depending on the affinity to these PBPs, on the affinity to these PBPs, varying amounts of varying amounts of endotoxinsendotoxins are are liberated from the gm-ve bacteria liberated from the gm-ve bacteria at at exposure to these antibioticsexposure to these antibiotics..

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Beta-lactam antibiotics with affinity Beta-lactam antibiotics with affinity for for PBP1PBP1, lead to , lead to rapid killing rapid killing without additional releasewithout additional release ofof endotoxinendotoxin whereas antibiotics with whereas antibiotics with selective affinityselective affinity for for PBP2PBP2, lead to , lead to conversion of the bacteria to round conversion of the bacteria to round cells, cells, spheroplastsspheroplasts, , with loss ofwith loss of viabilityviability but but withoutwithout cell wall cell wall destruction and excessive destruction and excessive endotoxin release.endotoxin release.

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Binding to Binding to PBP3PBP3, causes , causes selective inhibitionselective inhibition of of septationseptation and and continuingcontinuing bacterialbacterial elongationelongation with with formation of longformation of long filamentsfilaments and a and a subsequentsubsequent increased endotoxinincreased endotoxin production. Thus, production. Thus, the release ofthe release of high amounts ofhigh amounts of endotoxinendotoxin is is mainly associated with PBP3 mainly associated with PBP3 bindingbinding..

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Examples of antibiotics that are Examples of antibiotics that are selective for PBP1selective for PBP1 of E.coli are of E.coli are cephaloridinecephaloridine and and cefsulodin.cefsulodin.

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CeftazidimeCeftazidime, at high , at high concentrations binds to concentrations binds to PBP1PBP1..

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AntibioticsAntibiotics selective selective for for PBP2PBP2 are are mecillinammecillinam, , clavulanic clavulanic acidacid, and , and imipenemimipenem, and , and carbapenemcarbapenem..

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CefuroximeCefuroxime, , cefotaxime, cefotaxime, piperacillinpiperacillin , , mezlocillinmezlocillin and and aztreonamaztreonam bind to bind to PBP3PBP3 and and are associated with are associated with antibiotic-antibiotic-induced endotoxin release.induced endotoxin release.

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Antibiotics Antibiotics selectiveselective for for PBP3PBP3 at at low concentrations are low concentrations are cephalexincephalexin, , cefotaximecefotaxime, , ceftazidimeceftazidime, and , and cefuroximecefuroxime, , and and meropenemmeropenem..

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The The quinolonesquinolones inhibit protein inhibit protein synthesis via synthesis via inhibition ofinhibition of bacterial DNA synthesisbacterial DNA synthesis, but , but they have been associated with they have been associated with a substantial a substantial endotoxinendotoxin release.release.

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AminoglycosidesAminoglycosides inhibit inhibit protein synthesis, which results protein synthesis, which results in rapid killingin rapid killing without without excessive excessive endotoxinendotoxin release. They may release. They may even even reduce the endotoxin reduce the endotoxin liberationliberation induced by beta- induced by beta-lactam antibiotics.lactam antibiotics.

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It is probably an advantage to It is probably an advantage to add anadd an aminoglycoside aminoglycoside to the to the beta-lactambeta-lactam antibiotic for the antibiotic for the treatment oftreatment of severe infections severe infections such as such as progressing severeprogressing severe sepsissepsis and and septic shock.septic shock.

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ImipenemImipenem and and aminoglycosidesaminoglycosides seem to be seem to be antibiotics with only antibiotics with only modest modest endotoxin-liberatingendotoxin-liberating abilities. abilities. Thus they can be added to beta-Thus they can be added to beta-lactams.lactams.

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ConclusionConclusion

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The choice of antibiotic The choice of antibiotic classclass and and dosedose may important in the may important in the severely ill septic patient in severely ill septic patient in whom additional toxin release whom additional toxin release could be deleterious.could be deleterious.

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CefuroximeCefuroxime, , netilmicinnetilmicin and and ciprofloxacinciprofloxacin may be may be administered safely at administered safely at early early stages of sepsisstages of sepsis..

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Polymyxin B,Polymyxin B, gentamicingentamicin, , amikacinamikacin, , tobramycintobramycin can can neutralize the effect of neutralize the effect of endotoxinendotoxin..

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AMT selective for PBP1 and 2AMT selective for PBP1 and 2

CephalorlidineCephalorlidine CefsulodinCefsulodin Ceftazidime Ceftazidime

(HC).(HC).

CarbapenemsCarbapenems MecillinamMecillinam Clavulanic acidClavulanic acid ImipenemImipenem AminoglycosideAminoglycoside

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AMT selective for PBP3AMT selective for PBP3

CefuroximeCefuroxime CefotaximeCefotaxime PiperacillinPiperacillin MezlocillinMezlocillin CephaloxinCephaloxin CeftazidimeCeftazidime MeropenemMeropenem QuinolonesQuinolones

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One should One should startstart with a with a low low dosedose of antibiotic ( of antibiotic (hit gentlyhit gently) ) instead of instead of hithit vigorouslyvigorously..

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ReferencesReferences

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Editorial: Definition of Sepsis: Not Editorial: Definition of Sepsis: Not quite time to dump SIRS? quite time to dump SIRS? Critical Critical Care MedCare Med. 30(3):706 (2002).. 30(3):706 (2002).

Prins JM et al.: Clinical Relevance Prins JM et al.: Clinical Relevance of Antibiotic-induced Endotoxin of Antibiotic-induced Endotoxin Release. Release. Antimicrobial Agents Antimicrobial Agents and Chemotherapyand Chemotherapy..

38:1211 (1994).38:1211 (1994).

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Hjerdt-Goscindki Gunilla: Hjerdt-Goscindki Gunilla: Antibiotic-induced Bacterial Antibiotic-induced Bacterial Toxin Release-Inhibition by Toxin Release-Inhibition by Protein Synthesis Inhibitors. Protein Synthesis Inhibitors. Comprehensive Summaries of Comprehensive Summaries of Uppsala Dissertation from the Uppsala Dissertation from the Faculty of Medicine 1292. Faculty of Medicine 1292. ACTA ACTA UNIVERSITATIS UNIVERSITATIS UPSALIENSIS.UPSALIENSIS.

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Perduis GE et al.: Antimicrobial Perduis GE et al.: Antimicrobial induced Endotoxaemia in induced Endotoxaemia in patients with sepsis in the field patients with sepsis in the field of acute pyelonephritis. of acute pyelonephritis. Journal Journal ofof Postgraduate Medicine.Postgraduate Medicine. 49(2):114 (2003).49(2):114 (2003).

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Van Amersfoot ES et al: Van Amersfoot ES et al: Receptors, Mediators, and Receptors, Mediators, and Mechanisms Involved in Mechanisms Involved in Bacterial Sepsis and Septic Bacterial Sepsis and Septic Shock. Shock. Microbiology ReviewMicrobiology Review. . 7:379 (2003).7:379 (2003).

Silverman MH and Ostro MJ: Silverman MH and Ostro MJ: Bacterial Endotoxin in Human Bacterial Endotoxin in Human Disease.Disease.

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Thank YouThank You

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