Antibiotic prescribing practices in surgery · Infections caused by antibiotic-resistant bacteria...

Antibiotic prescribing practices in surgery

Global Alliance for Infections in Surgery

Antibiotic prescribing practices in surgery

Contents

Antimicrobial resistance 4

Antibiotics in surgery 7

Which interventions do improve antibiotic prescribing practices? 20

2Global Alliance for Infections in Surgery

3

Preface

Appropriate use of antibiotics should be integral to good clinical practice andstandards of care. However appropriate antibiotic prescribing practices areoften inadequate and a great gap exists between the best evidence andclinical practice across the surgical pathway.We hope this manual will draw attention to the need to change practices.

Massimo Sartelli



Antimicrobialresistance

4


Antimicrobial resistance

Antimicrobial resistance (AMR) is one of the greatest threats to public health,sustainable development and security worldwide. Its prevalence has increasedalarmingly over the past decades.Infections caused by antibiotic-resistant bacteria continue to be a challenge. Rice in2008 coined the acronym of “ESKAPE” pathogens including Enterococcus faecium,Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii,Pseudomonas aeruginosa, and Enterobacter species to emphasize that thesebacteria currently cause the majority of hospital infections and effectively “escape”the effects of antibacterial drugs. These organisms are increasingly multi-drug-(MDR), extensive-drug- (XDR) and pan-drug- resistant (PDR) and this process isaccelerating globally.Combating resistance has become a top priority for global policy makers and publichealth authorities. New mechanisms of resistance continue to emerge and spreadglobally, threatening our ability to manage common infections. Antibacterial use inanimal and agricultural industries aggravates selective pressure on microbes. A OneHealth approach is required urgently.The burden of AMR is difficult to quantify in some regions of the world becauseenhanced surveillance requires personnel, equipment and financial resources thatare not always available. However, the worldwide impact of AMR is significant interms of economic and patient outcomes.The global nature of AMR calls for a global response, both in the geographic senseand across all involved healthcare sectors. The impact of AMR worldwide issignificant, both in economic terms and patient outcomes, as it may:

Lead to some infections becoming untreatable or requiring antimicrobials of lastresort when the treatment is mandatory.

Increase length of hospital stay, morbidity, mortality and treatment cost.


The World Health Organization (WHO) endorsed a global action plan to tackleantimicrobial resistance. It sets out five strategic objectives:

To improve awareness and understanding of antimicrobial resistanceTo strengthen knowledge through surveillance and researchTo reduce the incidence of infectionTo optimize the use of antimicrobial agentsTo develop the economic case for sustainable investment that takes account of theneeds of all countries, and increase investment in new medicines, diagnostic tools,vaccines and other interventions.

Antibiotic agents can be lifesaving when treating patients with bacterial infectionsbut are often used inappropriately, specifically when unnecessary or whenadministered for excessive durations or without consideration of pharmacokineticprinciples. Large variations in antibiotic consumption exist between countries, andwhile excessive use remains a major problem in some areas of the world,elsewhere there is lack of access to many antimicrobial agents. AMR is a naturalphenomenon that occurs as microbes evolve. Human activities have acceleratedthe pace at which bacteria develop and disseminate resistance. Inappropriate useof antibiotic agents in humans and food producing animals, as well as poorinfection prevention and control practices, contribute to the development andspread of AMR.Although most physicians are aware of the problem of antimicrobial resistance,most underestimate this problem in their own hospital and prescribeinappropriately antibiotics. They can help tackle resistance by:

Enhancing infection prevention and controlControlling the source of infection when it is neededPrescribing antibiotics only when they are truly requiredPrescribing appropriate antibiotic(s) with adequate dosages to treat the infectionsUsing the shortest duration of antibiotics based on evidence of guidelinesEducating the communities in which we work of the need to use antibiotics wisely.

Antibiotics in surgery

Global Alliance for Infections in Surgery 7


Antibiotics use: finding the right balance

Clinicians should always optimize antibiotic management to maximise clinicaloutcome and minimize emergence of the development of resistance and theselection of resistant pathogens. The necessity of formalized systematic approachesto the optimization of antibiotic therapy in the setting of surgical general surgeryunits worldwide, both for elective and emergency admissions, has becomeincreasingly urgent.


Appropriate use of antibioticsis an integral part of

good clinical practice

Important considerations when prescribing antimicrobial therapy includeobtaining an accurate diagnosis of infection; understanding the differencebetween prophylaxis, empiric and targeted therapy; prescribing antibiotics forthe shortest duration; understanding antibiotics characteristics (such aspharmacodynamics and pharmacokinetics); accounting for host characteristicsthat influence antimicrobial activity; and in turn, recognizing the adverseeffects of antimicrobial agents on the host.

Antibiotics in surgery


Antibiotic prophylaxis

Systemic antibiotic prophylaxis (AP) is one of the most important componentof a perioperative infection prevention strategy. The use of AP contributesconsiderably to the total amount of antibiotics used in hospitals and may beassociated with increases in antibiotic resistance and healthcare costs.Although AP plays a pivotal role in reducing the rate of surgical siteinfections, other factors such as attention to basic infection-controlstrategies may have a strong impact on surgical site infections rates.Perioperative surgical AP should be recommended for operative proceduresthat have a high rate of postoperative wound infection or when foreignmaterial is implanted.Prophylactic antibiotic agents should be nontoxic and inexpensive and havein vitro activity against the common organisms that cause postoperativewound infection after a specific surgical procedure.Therapeutic concentrations of antibiotics should be present in the tissuethroughout the all period that the wound is open.


Principles of appropriate antibiotic prophylaxis

Antibiotic agents alone are unable to prevent surgical site infections.Strategies to prevent surgical site infections should always include attentionto:• IPC strategies including correct and compliant hand hygiene practices• Meticulous surgical techniques and minimization of tissue trauma• Hospital and operating room environments• Instrument sterilization processes• Peri-operative optimization of patient risk factors• Peri-operative temperature, fluid, and oxygenationmanagement• Targeted glycemic control• Appropriate management of surgical wounds

Antibiotic prophylaxis should be administered for operative procedures thathave a high rate of postoperative surgical site infection, or when foreignmaterials are implanted.

Antibiotic agents given as prophylaxis should be effective against the aerobicand anaerobic pathogens most likely to contaminate the surgical site—i.e.,gram-positive skin commensals or normal flora colonizing the incisedmucosae.

Antibiotic prophylaxis should be administered within 120 minutes before theincision. Administration of the first dose of antibiotic agents beginningwithin 30 to 60 minutes before surgical incision, however, is recommendedfor most antibiotic agents (e.g., cefazolin), to ensure adequate serum andtissue concentrations during the period of potential contamination. Obesepatients ‡120 kg require higher doses of antibiotic agents.


13

A single dose generally is sufficient. Additional antibiotic doses should beadministered intra-operatively for procedures >2–4 hours (typically whereduration exceeds two half-lives of the antibiotic) or with associatedsignificant blood loss (>1.5 L).

There is no evidence to support the use of postoperative antibioticprophylaxis.

Each institution is encouraged to develop guidelines for proper surgicalprophylaxis.


Antibiotic selection for empirical therapy

Antibiotics should be used after a treatable infection has been recognized orwhen there is a high degree of suspicion for infection. Initial antimicrobialtherapy is typically empirical in nature because they need immediatetreatment (especially in critically-ill patients), and microbiological data(culture and susceptibility results) usually requires ≥24 h for theidentification of pathogens and antibiotic susceptibility patterns.Isolation and identification of bacterial strains take more time, and results ofantibiotic susceptibility are usually only available after 48 h and later.The decision tree for the empiric antibiotic regimen should depend mainlyon three factors: presumed pathogens involved and risk factors for majorresistance patterns, clinical patient's severity and presumed/identifiedsource of infection.Generally, the most important factors in predicting the presence of resistantpathogens in surgical infections is acquisition in a healthcare setting(particularly if the patient becomes infected in the ICU or has beenhospitalized for more than 1 week), corticosteroid use, organtransplantation, baseline pulmonary or hepatic disease, and previousantimicrobial therapy.Previous antimicrobial therapy is one of the most important risk factors forresistant pathogens.Knowledge of local rates of resistance and the risk factors that suggestresistant bacteria should be involved as essential components of the clinicaldecision-making process when deciding on which antibiotic regimen to usefor empiric treatment of infection.Especially in critically ill patients inappropriate therapy may have a strongnegative impact on outcome. An ineffective or inadequate antimicrobialregimen is one of the variables more strongly associated with unfavorableoutcomes in critically ill patients. Broad empiric antimicrobial therapy shouldbe started as soon as possible in patients with organ dysfunction (sepsis) andseptic shock. International guidelines for the management of sepsis andseptic shock (the Surviving Sepsis Campaign) recommend intravenouslyadministered antibiotics as soon as possible and in any case within the firsthour of onset of sepsis and the use of broad-spectrum agents with adequatepenetration of the presumed site of infection.


Dosage

The antibiotic dosing regimen should be established depending on host factorsand properties of antibiotic agents. Antibiotic pharmacokinetics describes thefundamental processes of absorption, distribution, metabolism, andelimination and the resulting concentration-versus-time profile of an agentadministered in vivo. The achievement of appropriate target siteconcentrations of antibiotics is essential to eradicate the relevant pathogen.Suboptimal target site concentrations may have important clinicalimplications, and may explain therapeutic failures, in particular, for bacteriafor which in vitro MICs are high. Antibiotics typically need to reach a site ofaction outside the plasma. This requires the drug to pass through the capillarymembranes. Disease and drug-related factors can contribute to differentialtissue distribution.Knowledge of the pharmacokinetic and pharmacodynamic antibioticproperties of each drug including (inhibition of growth, rate and extent ofbactericidal action, and post-antibiotic effect) may provide a more rationaldetermination of optimal dosing regimens in terms of the dose and the dosinginterval. Optimal use of the pharmacokinetic/pharmacodynamic relationshipof anti-infective agents is important for obtaining good clinical outcomes andreduction of resistance. Dosing frequency is related to the concept of time-dependent versus concentration-dependent killing. Beta-lactams exhibit time-dependent activity and exert optimal bactericidal activity when drugconcentrations are maintained above the MIC. Therefore, it is important thatthe serum concentration exceeds the MIC for appropriate duration of thedosing interval for the antimicrobial and the organism. Higher frequencydosing, prolonged infusions and continuous infusions have been utilized toachieve this effect. In contrast, antibiotics such as aminoglycosides exhibitconcentration-dependent activity and should be administered in a once dailymanner (or with the least possible number of daily administrations) in orderto achieve high peak plasma concentrations. With these agents, the peakserum concentration, and not the time the concentration remains above theMIC, is more closely associated with efficacy. In terms of toxicity,aminoglycosides nephrotoxicity is caused by a direct effect on the renal cortexand its uptake saturation. Thus, an extended interval dosing strategy reducesthe renal cortex exposure to aminoglycosides and reduces the risk ofnephrotoxicity.


In patients with septic shock, administering an optimal first dose is probablyas equally important as to the timing of administration. This optimal first dosecould be described as a loading, or front-loaded dose and is calculated fromthe volume of distribution (Vd) of the drug and the desired plasmaconcentration. The Vd of hydrophilic agents (which disperse mainly in watersuch as beta-lactams, aminoglycosides and glycopeptides) in patients withseptic shock may be altered by changes in the permeability of themicrovascular endothelium and consequent alterations in extracellular bodywater. This may lead to lower than expected plasma concentrations during thefirst day of therapy resulting in sub-optimal achievement of antibiotic levels.In the setting of alterations in the volume of distribution, loading doses and/ora higher overall total daily dose of beta-lactams, aminoglycosides, orglycopeptides are often required to maximize the pharmodynamics ensuringoptimal drug exposure to the infection site in patients with sepsis or septicshock.Once an appropriate initial loading dose is achieved, the antibiotic regimenshould be reassessed, at least daily, because pathophysiological changes maysignificantly affect drug availability in the critically ill patients. Lower thanstandard dosages of renally excreted drugs must be administered in thepresence of impaired renal function, while higher than standard dosages ofrenally excreted drugs may be needed for optimal activity in patients withglomerular hyperfiltration. It should be noted that in critically ill patients,plasma creatinine is an unreliable marker of renal function.


Duration

Duration of therapy should be shortened as much as possible unless there arespecial circumstances that require prolonging antimicrobial therapy such asimmunosuppression, or ongoing infections. Oral antimicrobials, can substituteIV agents as soon as the patient is tolerating an oral diet so as to minimize theadverse effects which are associated with intravenous access devices. Wherepossible, conversion to oral antimicrobial agents having high oralbioavailability (e.g. fluoroquinolones) should be considered. Patients withintra-abdominal infections who have signs of sepsis beyond 5 to 7 days oftreatment warrant aggressive diagnostic investigation to determine if anongoing uncontrolled source of infection or antimicrobial treatment failure ispresent. In the management of critically ill patients with sepsis and septicshock clinical signs and symptoms as well as inflammatory response markerssuch as procalcitonin, although debatable, may assist in guiding antibiotictreatment.


Principles of appropriate antibiotic therapy

The source of infection should always be identified and controlled as soon aspossible.

Antibiotic empiric therapy should be initiated after a treatable surgicalinfection has been recognized, because microbiologic data (culture andsusceptibility results) may not be available for up to 48–72 hours to guidetargeted therapy.

In critically ill patients, empiric broad-spectrum therapy to cover the mostlikely pathogens should be initiated as soon as possible after a surgicalinfection has been recognized. Empiric antimicrobial therapy should benarrowed once culture and susceptibility results are available and adequateclinical improvement is noted.

Empiric therapy should be chosen on the basis of local epidemiology,individual patient risk factors for MDR bacteria and Candida spp., clinicalseverity, and infection source.

Specimens for microbiologic evaluation from the site of infection are alwaysrecommended for patients with hospital-acquired or with community-acquired infections at risk for resistant pathogens (e.g., previousantimicrobial therapy, previous infection or colonization with a MDR, XDR,and PDR pathogen) and in critically ill patients. Blood cultures should beperformed before the administration of antibiotic agents in critically illpatients.

6. The antibiotic dose should be optimized to ensure that PK-PD targets areachieved. This involves prescribing an adequate dose, according to the mostappropriate and right method and schedule to maximize the probability oftarget attainment.

The appropriateness and need for antimicrobial treatment should be re-assessed daily.


Once source control is established, short courses of antibiotic therapy are aseffective as longer courses regardless of signs of inflammation.

Failure of antibiotic therapy in patients having continued evidence of activeinfection may require a reoperation for a second source control intervention.

Biomarkers such as procalcitonin may be useful to guide duration andcessation of antibiotic therapy in critically ill patients.

Clinicians with advanced training and clinical experience in surgicalinfections should be included in the care of patients with severe infections.

12. The infection prevention and control measures combined withantimicrobial stewardship programs should be implemented in all hospitalsworldwide. These interventions and programs require regular, systematicmonitoring to assess compliance and efficacy.

Monitoring of antibiotic consumption should be implemented and feedbackprovided to all ASP team members regularly along with resistancesurveillance data and outcome measures


Which interventions do

improve antibiotic prescribing practices?

Global Alliance for Infections in Surgery 20

Significant data support the importance of antibiotic prescribing practices forpatients with surgical infections, in critically ill and non-critically ill patientsand in community and hospital-acquired infections. Prescribing practicesmay influence the outcome and cost of treatment as well as the risk of someemerging infections (such as C. difficile) and resistant pathogens in theindividual patient and the broader environment.The necessity of formalized systematic approaches to the optimization ofantibiotics use in the setting of surgical units worldwide, both forprophylaxis and therapy, has become increasingly urgent.Interventions to improve antibiotic prescribing practices for patients withsurgical infections should be directed at two different levels:

Patient level – which includes clinical severity, epidemiological exposures,PK/PD factors, comorbidities, prior antibiotic exposure, prior infection, orcolonization with MDROs and infection source.

Hospital level – which includes presence of in-hospital antimicrobialstewardship programs, availability of local guidelines and updatedmicrobiological data, infection and control control policy, educationalactivities, and structural resources (like computer-assisted order entry).


Components of antibiotic prescribing practices at patient level that mayinfluence outcome and the risk of developing emerging infections andantibiotic resistant infections include:

Adequacy of antibiotic therapy/prophylaxis,Time to initial antibiotic therapy/prophylaxis,Appropriate pharmacokinetic dosing,Reassessment of antibiotic therapy,Length of treatment, andAvoidance of unnecessary antibiotic therapy.

A growing body of evidence demonstrates that hospital based programsdedicated to improving antibiotic use, commonly referred to as “AntibioticStewardship Programs” (ASPs), can both optimize the treatment ofinfections and reduce adverse events associated with antibiotic use.Despite current ASPs being advocated by infectious disease specialists anddiscussed by national and international policy makers, ASPs coverageremains limited to only certain hospitals as well as specific service lineswithin hospitals. ASPs incorporate a variety of strategies to optimizeantibiotic use in the hospital yet the exact set of interventions essential toASP success remains unknown. Promotion of ASPs across clinical practice iscrucial to their success to ensure standardization of antibiotic use within aninstitution. The preferable means of improving antimicrobial stewardship isto involve a comprehensive program that incorporates collaboration amongvarious specialties within a healthcare institution.


Successful ASPs should focus on collaboration between all healthcareprofessionals to shared knowledge and widespread diffusion of practice.Involvement of prescribing physicians in ASPs may rise their awareness onantimicrobial resistance.It is essential for an ASP to have at least one member who is an infectiousdiseases specialist. Pharmacists with advanced training or longstandingclinical experience in infectious diseases are also key actors for the designand implementation of the stewardship program interventions. In anyhealthcare setting, a significant amount of energy should be spent oninfection prevention and control. Infection control specialists and hospitalepidemiologists should be always included in the ASPs to coordinate effortson monitoring and preventing healthcare-associated infections.Microbiologists should actively guide the proper use of tests and the flow oflaboratory results. Being involved in providing surveillance data onantimicrobial resistance, they should provide periodic reports onantimicrobial resistance data allowing the multidisciplinary team todetermine the ongoing burden of antimicrobial resistance in the hospital.Moreover, timely and accurate reporting of microbiology susceptibility testresults allows selection of more appropriate targeted therapy, and may helpreduce broad-spectrum antimicrobial use. Surgeons with adequateknowledge in surgical infections and surgical anatomy when involved in ASPsmay audit antibiotic prescriptions, provide feedback to the prescribers andintegrate best practices of antimicrobial use among surgeons, and act aschampions among colleagues implementing change within their own sphereof influence. Infections are the main factors contributing to mortality inintensive care units (ICU). Intensivists have a critical role in treatingmultidrug resistant organisms in ICUs in critically ill patients. They have acrucial role in prescribing antimicrobial agents for the most challengingpatients and are at the forefront of a successful ASP. Emergency departments(EDs) represent a particularly important setting for addressing inappropriateantimicrobial prescribing practices, given the frequent use of antibiotics inthis setting that sits at the interface of the community and the hospital.Therefore also ED practitioners should be involved in the ASPs. Withoutadequate support from hospital administration, the ASP will be inadequateor inconsistent since the programs do not generate revenue. Engagement ofhospital administration has been confirmed as a key factor for bothdeveloping and sustaining an ASP.


Finally, an essential participant in antimicrobial stewardship who has beenoften unrecognized and underutilized is the “staff nurse.” Although the roleof staff nurses has not formally been recognized in guidelines forimplementing and operating antimicrobial ASPs they perform numerousfunctions that are integral to successful antimicrobial stewardship. Nursesare antibiotic first responders, central communicators, as well as 24-hourmonitors of patient status.


Multifaceted interventions are more likely to improve antibiotic prescribingpractices than simple, passive interventions. Although didactic educationalprograms alone are generally ineffective, education is crucial inimplementing antibiotic prescribing practices among prescribers. Sincephysicians are primarily responsible for the decision to useantibiotics, educating them and changing the attitudes and knowledge thatunderlie their prescribing behavior may be crucial for improving antibioticprescription.Education of all health professionals involved in antibiotic prescribing shouldbegin at undergraduate level and be consolidated with further trainingthroughout the postgraduate years. Hospitals are responsible for educatingclinical staff about their local antimicrobial stewardship programs.Active education techniques, such as academic detailing, consensus buildingsessions and educational workshops, should be implemented in eachhospital worldwide according to its own resources. Efforts to improve activeeducational programs raising awareness of the correct use of antibiotics arestrongly required. The direct involvement of the prescribers in theseprograms may be a way to fight the cognitive dissonance that blocksprescribers in this process.


Enhance infection

prevention and control

Prescribe antibiotics when they are truly needed

Use antibiotics

appropriately

Control the source of infection when it is needed

Together we can impact millions of people!


References

Rice LB. Federal funding for the study of antimicrobial resistance innosocomial pathogens: no ESKAPE. J Infect Dis. 2008;197:1079–1081.

Sartelli M, Weber DG, Ruppé E, Bassetti M, Wright BJ, Ansaloni L, et al.Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA). World J Emerg Surg. World J Emerg Surg.2016 Jul 15;11:33.

Sartelli M, Labricciosa FM, Barbadoro P, Pagani L, Ansaloni L, Brink AJ, et al.The Global Alliance for Infections in Surgery: defining a model forantimicrobial l stewardship-results from an international cross-sectionalsurvey. World J Emerg Surg. 2017 Aug 1;12:34.

Goff DA, Kullar R, Goldstein EJC, Gilchrist M, Nathwani D, Cheng AC, et al. Aglobal call from five countries to collaborate in antibiotic stewardship: unitedwe succeed, divided we might fail. Lancet Infect Dis. 2017 Feb;17(2):e56-e63.

Barlam TF, Cosgrove SE, Abbo LM, MacDougall C, Schuetz AN, Septimus EJ, etal. Implementing an antibiotic stewardship program: guidelines by theInfectious Diseases Society of America and the Society for HealthcareEpidemiology of America. Clin Infect Dis. 2016;62:e51–e77.

Sartelli M, Weber DG, Ruppé E, Bassetti M, Wright BJ, Ansaloni L, et al.Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA). World J Emerg Surg. 2016;11:33.


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