Section 10: Antimicrobial Stewardship And Clostridium .

Guide to Preventing Clostridium difficile InfectionsSection 10: Antimicrobial Stewardshipand Clostridium difficile Infection: APrimer for the Infection PreventionistAntimicrobial stewardship may be a relatively newaddition to the job responsibilities of the IP. Thediscussion of antimicrobial use and its impact onpatients in all healthcare settings in this section isfocused solely within the context of C. difficile. Thebroad term “antimicrobial stewardship” is used inplace of “antibiotic stewardship,” as development ofa stewardship program ideally includes all antiviraland antifungal agents as well as antibiotics. Asantibiotics are the antimicrobial agents effectiveagainst bacteria, the term antibiotic is used mostoften in the discussion of C. difficile infection.Role of antibiotic use in theoccurrence of CDIBecause CDI is nearly always a complication ofantibiotic use, the development of a healthcarefacility program to ensure appropriate antibioticuse is considered an important preventionintervention.1-4 Figure 10.1 represents the differentphases of C. difficile infection of the colon, startingwith a normal colonic environment (phase A)through the development of pseudomembranouscolitis (phase D).The most important protection mechanismagainst CDI in humans is the normal gut flora.These bacteria reside in the gastrointestinaltract and prevent pathogens from attaching,multiplying, and producing disease.5,6Normal colonic floraThe hundreds of trillions of bacteria thatmake up our normal gastrointestinal floraare an important defense mechanism againstintestinal pathogens.5,6 This ecosystem ofbacteria is called the human gastrointestinalmicrobiome. Some of the normal bacterialflora is attached to receptors on the epithelialcells in the colon, whereas other bacteria arepresent in the lumen of the gastrointestinaltract (Figure 10.1, phase A). In order for C.difficile to maintain a presence, the normalflora must be depleted. Due to the diversebacterial species in the human colon, it hasbeen difficult to identify which particularorganisms are responsible for the protectiveeffect against C. difficile. The exact mechanismby which an intact gastrointestinal floraprotects against C. difficile colonization is notcompletely understood, but several mechanismshave been proposed. To cause colonizationor an infection, C. difficile needs to attach toreceptors in the human gastrointestinal cells. Ifthese receptors are occupied by organisms of thenormal gastrointestinal flora, C. difficile strainsreaching the gut mucosa will have no place forattachment and will not be able to survive.In addition to preventing colonization bycompeting for attachment sites, the normalflora may prevent colonization by deprivingC. difficile of essential nutrients. The normalflora may also antagonize C. difficile throughthe production of substances that inhibit orkill C. difficile. Antibiotics may also alter thecolonic microenvironment by changing the localprotein composition or amount of local mucusproduction, which may aid the survival of C.difficile.Association for Professionals in Infection Control and Epidemiology73

Guide to Preventing Clostridium difficile InfectionsFigure 10.1. Phases of pathogenesis of C. difficile colitis.Phase APhase BPhase CPhase DNormal GIFlora & MucosaC diffColonizationC diff ToxinProductionC diffColitisC diffC diff toxinsA&BAntibioticsPseudomembraneWhite blood cellsFigure 12.1. Phases of the pathogenesis of C. difficile colitisunder the anaerobic conditions of the colon, 5)Antibiotic collateral damageantibiotic dose, 6) the route of administration,As mentioned previously, the normaland 7) antibiotic excretion in the bile. Antibioticgastrointestinal flora are the main protectioncollateral damage is largely due to the killing ofmechanism of the host to prevent colonizationnormal colonic flora, but antibiotics may causeand infection with pathogens such as C. difficile. Ifcollateral damage by altering other colonic factorsthis microbiome is disrupted (Figure 10.1, phasebeyond bacteria that may play an important roleB), C. difficile can attach to the gastrointestinalin local defense mechanisms against C. difficile. Inepithelial cells, produce toxin (Figure 10.1,the next sections, we review the major factors ofphase C), and cause disease (Figure 10.1, phaseantibiotics that play a role in the disruption of theD). Because antibiotics kill bacteria and are notnormal colonic flora, leading to colonization and/specific to one particular bacterium, they all haveor infection with this pathogen.the ability to disrupt the balance of bacteria inthe microbiome. The propensity of a particularantibiotic to alter the gastrointestinal flora can beAntibiotic spectrum of activitydefined as antibiotic “collateral damage.”7and duration of therapyThe extent of damage depends upon a numberof antibiotic-specific factors such as: 1) thespectrum of activity, 2) duration of therapy, 3) theamount of the antibiotic that reaches the colonicenvironment, 4) the activity of the antibiotic74All antibiotics produce disruption of the colonicflora, but they are not equal in their capability tocause collateral damage. The first two elementsthat need to be considered when evaluating therisk for CDI produced by a particular antibioticAssociation for Professionals in Infection Control and Epidemiology

Guide to Preventing Clostridium difficile Infectionsinclude antibiotic spectrum and duration.8 Thefirst is the level of risk produced by a particularantibiotic, defined by the antibiotic spectrumof activity. As the titles suggest, broad-spectrumantibiotics kill a variety of different bacteria,whereas narrow-spectrum antibiotics kill a muchsmaller variety. In this regard some antibiotics willplace the patient at low, intermediate, or high riskfor development of CDI.The second factor to be considered is thenumber of days that the patient will be at riskfor development of CDI. Greatest days at riskfor colonization occur during the time that thepatient is receiving antibiotic therapy and up to5 to 10 days after discontinuation of antibiotics,although the risk may extend for 3 months ormore. The longer a patient is treated with anantibiotic, the more normal flora will be killed.8These two factors combined are critical in thepathogenesis of C. difficile. For example, a patientwho receives a narrow-spectrum antibiotic for lessthan 1 day, such as one dose of a first-generationcephalosporin for surgical prophylaxis, willbe considered to have a low level of risk anda short duration of risk. If the same patient isgiven surgical prophylaxis with an unnecessarilybroad-spectrum antibiotic (e.g., a carbapenem),the level of risk can move from low to highwithout any additional clinical benefit from thatbroad-spectrum antibiotic. Extension of surgicalprophylaxis with a first-generation cephalosporinfor multiple doses that continue beyond the dayof surgery will also increase the risk of CDI byincreasing the number of days that the patientwill be at risk. Even though all antibiotic therapy,appropriate or inappropriate, will place the patientat risk for CDI, the prolonged use of broadspectrum antibiotics is an unnecessary additionalrisk factor that may be prevented.The most common inappropriate antibioticuse that places a patient at increased risk is thecontinuation of broad-spectrum antibiotics afterthe etiology of infection has been identified,and the pathogen is found to be susceptible toa narrower-spectrum antibiotic. For example,in a patient with a prolonged ICU stay thatdeveloped a ventilator-associated pneumonia(VAP), it would be appropriate to start empirictherapy with a broad-spectrum regimen to coverthe possibility of resistant Gram-positive as wellas Gram-negative bacteria (e.g., vancomycin pluspiperacillin/tazobactam). If respiratory or bloodcultures identify an MSSA as the etiology of VAP,the continuation of the initial broad-spectrumcoverage should be considered inappropriate. Int bileAntibiotics excreted in the bile at a highconcentration have been shown to deplete moreof the normal flora than those that are not. Thisis due to high intraintestinal concentrationsof these drugs. Antibiotic excretion in thebile may be considered a higher priority thanoral versus intravenous administration as well.Intravenous antibiotics excreted in the bile at highconcentrations may kill more of the normal florathan incompletely absorbed oral antibiotics.10,11Role of antimicrobialstewardship in prevention ofcolonization and infectionColonization with C. difficile may occur whenthe normal flora is depleted and the organismis introduced into the gastrointestinal tract.Interventions to improve the practice with regardto the previously mentioned factors will help toreduce the excessive depletion of the normal flora.However, antimicrobial stewardship practiceswill not prevent introduction of the organisminto the gastrointestinal tract. Basic infectionprevention practices are necessary for this essentialcomponent of C. difficile prevention.Once a patient is colonized with C. difficile, thepatient may progress to develop C. difficile colitisAssociation for Professionals in Infection Control and Epidemiology

Guide to Preventing Clostridium difficile Infectionsor may remain colonized without developingdisease. Lack of disease may be due to colonizationwith a C. difficile strain that does not producetoxins.12 Once the patient is colonized with anontoxigenic strain, the patient may be less likelyto be colonized with another strain—one that maybe toxigenic. It is considered that the initial strainmay occupy receptors than become unavailableto a new strain. The use of metronidazole in apatient colonized with a nontoxigenic C. difficilestrain may favor development of C. difficile colitisby killing the nontoxigenic strain and allowingcolonization and infection due to a toxigenicstrain. This is the reason behind laboratorytesting for C. difficile toxins as opposed to solelytesting for C. difficile antigens (e.g., glutamatedehydrogenase). Antigen testing does notdifferentiate between toxigenic and nontoxigenicstrains.13 Identification of the organism throughantigen testing alone will provide clinicians withunnecessary data and may result in unnecessaryantimicrobial treatment. However, a positive testfor C. difficile toxin in the stool is not by itselfindication for antibiotic therapy. A patient whois asymptomatic but has a positive C. difficiletest should be considered a carrier and antibiotictherapy is not indicated. The inappropriateuse of metronidazole or vancomycin may favordevelopment of disease or MDROs in a patientwho is only a carrier.Role of antimicrobialstewardship in treatment ofinfectionOnce a patient is diagnosed as having CDI,antimicrobial stewardship is important to achieveoptimal medical therapy. This is represented inthe C. difficile prevention activities (Figure 10.1)as the fourth level of intervention. There arethree strategies that can be considered for themanagement of a patient with C. difficile colitis:1) killing of C. difficile, 2) blocking toxin, and 3)restoring normal flora.Killing of C. difficile in the colon can be achievedwith the use of a number of antibiotics, mostFigure 10.2. Activities to prevent and manage C. difficile infection in healthcare settings.First Step: Antibioticcollateral damageSecond Step: C diffnosocomial exposureThird Step: C difftoxin productionFourth Step: ToxinhyperproductionFifth Step: Shock& Severe SepsisPatientNormal GI FloraPatientDisruption of GI FloraPatientC diff ColonizationPatientC diff ColitisPatientFulminant ColitisPatientDeath due to C diffC difficile Preventionand ol3Prevention ofInfection4AntimicrobialStewardshipOptimal5 Surgical TreatmentSentinel Event &6 Root Cause AnalysisFigure 10.2. Activities to preventand manageC. difficilein infectionin healthcaresettings.Associationfor ProfessionalsInfection Controland Epidemiology77