MANIFESTO for the appropriate use of antibiotics in healthcare…participating in World Antibiotic Awareness Week

Beginning with the discovery of penicillin by Alexander Fleming in the late 1920s, antibiotics have revolutionized the field of medicine. They have saved millions of lives each year, and have even been used prophylactically for the prevention of infectious diseases. However, we have now reached a crisis where many antibiotics are no longer effective. Such infections often result in an increased number of hospitalizations, more treatment failures and the persistence of drug-resistant pathogens. Antimicrobial resistance (AMR) has emerged as one of the principal public health problems of the 21st century. This has resulted in a public health crisis of international concern, which threatens the practice of modern medicine, animal health and food security. The substantial problem of AMR is especially relevant to antibiotic resistance, although antifungal resistance is increasing at an alarming rate. Although the phenomenon of AMR can be attributed to many factors, there is a well-established relationship between antibiotic prescribing practices and the emergence of resistant bacteria. Antibiotic overuse is occurring in multiple sectors (human, animal, agriculture). Bacteria faced with antibiotic selection pressure enhance their fitness by acquiring and expressing resistance genes, then sharing them with other bacteria and by other mechanisms, for example gene overexpression and silencing, phase variation. Most bacteria and their genes can move relatively easily within and between humans, animals and the environment and several interconnected human, animal and environmental habitats can contribute to the emergence, evolution and spread of AMR, and the health of these contiguous habitats may represent a risk to human health.

Although the current magnitude of the problem and the need for a one health approach, healthcare workers play a central role in preventing the emergence and spread of AMR. In clinical practice, on one hand we should offer optimal therapy for the individual patient under our care; on the other hand we should limit the impact of the antibiotic in order to prevent the selection of resistant pathogens and pathogenic bacteria such as C. difficile.

It is crucial that we have awareness of the burden of AMR and that understand that using antibiotics inappropriately may increase the likelihood of treatment failures and antimicrobial resistance. Below we report 10 principles for an appropriate use of antibiotics in healthcare.

Join us now as we embark on this global cause, by pledging support for this manifesto and accepting the responsibility for maintaining the effectiveness of current and future antibiotic agents.


Enhance infection prevention and control

Prevention is better than cure and it is important that all helthcare workers depend on evidence-based infection and control interventions to reduce demand for antibiotic agents by preventing healthcare associated infections from occurring in the first place, and making every effort to prevent transmission when they occur. The issues surrounding infection prevention and control are intrinsically linked with the issues associated with the use of antibiotic agents and the proliferation and spread of AMR. The vital work of the infection prevention and control and of the antimicrobial stewardship cannot be performed independently and requires interdependent and coordinated action across multiple and overlapping disciplines and clinical settings.


Control the source of infection

Source control encompasses all measures undertaken to eliminate the source of infection, reduce the bacterial inoculum and correct or control anatomic derangements to restore normal physiologic function. In critically ill patients with severe sepsis these principles can be applied at different times in the same patient. Appropriate source control is of outmost importance in the management of surgical infections. Intra-abdominal infections along with soft tissues infections are the sites where a source control is more feasible and more impactful. In these settings an appropriate source control can improve patients’ outcome and reduce antibiotic pressure allowing short course of antibiotic therapy. Source control generally involves drainage of abscesses or infected fluid collections, debridement of necrotic or infected tissues and definitive control of the source of contamination. As a general principle, every verified source of infection should be controlled as soon as possible. The level of urgency of treatment is determined by the affected organ(s), the relative speed at which clinical symptoms progress and worsen, and the underlying physiological stability of the patient. 


Prescribe antibiotics when they are truly needed

Antibiotics can be life-saving when treating bacterial infections but are often used inappropriately, specifically when unnecessary or when administered for excessive durations or without consideration of pharmacokinetic principles. Antibiotics should be used after a treatable infection has been recognized or when there is a high degree of suspicion for infection.


Prescribe the appropriate antibiotic(s) at the right time

The critical nature of the microbiology laboratory in infectious disease diagnosis calls for a close, positive working relationship between the physician/advanced practice provider and the microbiologists who provide enormous value to the healthcare team. Clinicians seek three basic truths from the clinical microbiology laboratory, i.e., (i) whether the patient is infected, (ii) if so, with what, and (iii) what will treat it. Effective antimicrobial stewardship is closely linked with the ability to make correct diagnosis. Incorrect diagnoses can lead not only to overuse or misuse of antibiotics, particularly the critical broad-spectrum antibiotics, but also to poor outcomes for patients resulting from failure to treat the actual infection present. Speed of diagnostic testing is also a key factor in effective antimicrobial stewardship. Typical turnaround time using traditional microbiological testing methods is 24 to 72 hours for pathogen identification, followed by additional hours for antibiotic susceptibility testing. Initial treatment decisions is typically made empirically before diagnostic testing results are available, especially in critically ill patients with sepsis and septic shock, in which appropriate empiric antibiotic therapy must be administered as soon as possible because delayed antibiotic therapy is strongly associated with increased mortality. Empirical antibiotic therapy should be based on local epidemiology, individual patient risk factors for difficult to treat pathogens, clinical severity of infection, and infection source. Knowledge of local rates of resistance should be an essential component of the clinical decision-making process when deciding on which antibiotic regimen to use for empiric treatment of the infection. An important key goal of antimicrobial stewardship can be achieved through faster and more accurate diagnostic testing—reducing time to appropriate antibiotics, reducing unnecessary use of antibiotics, and informing decisions regarding antibiotic de-escalation or discontinuation. Accordingly, the need to speed up diagnostic testing is a central theme in recent policy initiatives to combat AMR. One of the major goals for combating Antibiotic-Resistant Bacteria is to advance the development and use of rapid and innovative diagnostic tests for identifying and characterizing resistant bacteria, to improve their treatment, enhance infection control, and facilitate outbreak detection and response.


Prescribe antibiotics with adequate dosages

The antibiotic dosing regimen should be established depending on host factors and properties of antimicrobial agents. Antibiotic pharmacodynamics integrates the complex relationship between organism susceptibility and patient pharmacokinetics. Antibiotic pharmacokinetics describes the fundamental processes of absorption, distribution, metabolism, and elimination and the resulting concentration-versus-time profile of an agent administered in vivo. The achievement of appropriate target site concentrations of antibiotics is essential to eradicate the relevant pathogen. Suboptimal target site concentrations may have important clinical implications, and may explain therapeutic failures, in particular, for bacteria for which in vitro MICs are high. Antibiotics typically need to reach a site of action outside the plasma. This requires the drug to pass through the capillary membranes. Disease and drug-related factors can contribute to differential tissue distribution. Commonly encountered situations where pharmacokinetics change and dosing individualization may be necessary include renal and hepatic dysfunction. Dose reductions may be necessary to prevent accumulation and toxicity in patients with reduced renal or hepatic function. Knowledge of the pharmacokinetic and pharmacodynamic antimicrobial properties of each drug including (inhibition of growth, rate and extent of bactericidal action, and post-antibiotic effect) may provide a more rational determination of optimal dosing regimens in terms of the dose and the dosing interval. Optimal use of the pharmacokinetic/pharmacodynamic relationship of anti-infective agents is important for obtaining good clinical outcomes and reduction 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 drug concentrations are maintained above the MIC. Therefore, it is important that the serum concentration exceeds the MIC for appropriate duration of the dosing interval for the antimicrobial and the organism. Higher frequency dosing, prolonged infusions and continuous infusions have been utilized to achieve this effect. In contrast, antibiotics such as aminoglycosides exhibit concentration-dependent activity and should be administered in a once daily manner (or with the least possible number of daily administrations) in order to achieve high peak plasma concentrations.


Reassess treatment when culture results are available

Reassessment and de-escalation of antibiotic therapy based on microbiologic culture, susceptibility testing, and clinical improvement not only promote antimicrobial stewardship but may be associated with improved outcomes in serious infections. The patient should be always reassessed when the results of microbiological testing are available. The results of microbiological testing may have great importance for the choice of therapeutic strategy of every patient, in particular in the adaptation of targeted antimicrobial treatment. They provide an opportunity to expand antimicrobial regimen if the initial choice was too narrow but also allow de-escalation of antibiotic therapy if the empirical regimen was too broad. Antibiotic de-escalation has been associated with lower mortality rates in ICU patients and is now considered a key practice for antimicrobial stewardship purposes. Transitioning to less toxic and/or more effective antibiotics (e.g., use of beta-lactams instead of vancomycin to treat confirmed MSSA) and reducing selection pressure for multidrug-resistant nosocomial infections may explain some of the protective effects of de-escalation.


Use the shortest duration of antibiotics based on evidence

Duration of therapy should be shortened as much as possible unless there are special circumstances that require prolonging antimicrobial therapy such as immunosuppression, or ongoing infections. There is good evidence that shorter durations of antibiotics can reduce adverse effects associated with their use. Furthermore, systematic reviews have found that clinical outcomes are similar between short and long courses for many common infections. Given the relatively high rates of prescribing, we can all play a significant role in reducing the burden of inappropriate antibiotic use by prescribing short-course therapy when appropriate. Patients who have signs of sepsis beyond 5 to 7 days of treatment warrant aggressive diagnostic investigation to determine if an ongoing uncontrolled source of infection or antimicrobial treatment failure is present. In the management of critically ill patients with sepsis and septic shock clinical signs and symptoms as well as inflammatory response markers such as procalcitonin, although debatable, may assist in guiding antibiotic treatment. Among sepsis biomarkers, procalcitonin (PCT), a precursor of calcitonin, has been most widely studied to guide antibiotic duration in septic patients. PCT is undetectable in healthy states, but it is stimulated synergistically by the inflammatory mediators of host response, bacterial products, and necrotic body cells. Serum PCT levels rise rapidly in response to systemic inflammatory insults, with peak levels that correlated with the intensity of the stimulus. PCT has a short half-life (25–30 hours), and its levels decline rapidly with a resolution of inflammation. Those properties make it potentially useful in helping decide whether to stop antibiotics and when to stop antibiotics in clinically improving patients.


Support surveillance of HAIs and monitor of antibiotic consumption

Monitoring of antibiotic consumption should be implemented and feedback provided to all antimicrobial stewardship team members and to all prescribers regularly along with healthcare-associated infections (HAIs) surveillance data and measures. HAIs are a patient safety and quality of healthcare issue which contributes to poor patient outcomes and additional costs to the health care system. Surveillance to determine the incidence of HAIs is an important part of the strategy to minimise the occurrence of these infections. 


Educate staff

Education in antibiotic prescribing practice is fundamental. A range of factors such as diagnostic uncertainty, fear of clinical failture, time pressure or organisational contexts can complicate prescribing decisions. However, due to cognitive dissonance (recognising that an action is necessary but not implementing it), changing prescribing behaviour is extremely challenging. Efforts to improve educational programs are thus required and this should preferably be complemented by active interventions such as prospective audits and feedback to stimulate further change. It is also crucial to incorporate fundamental antimicrobial stewardship and infection prevention and control principles in under- and post graduate training at medical faculties to equip young doctors and other healthcare professionals with the required confidence, skills and expertise in the field of antibiotic management.


Support an interdisciplinary approach

Promotion of antimicrobial stewardship across clinical practice is crucial to their success to ensure standardization of antibiotic use within an institution. We propose that the best means of improving antimicrobial stewardship should involve collaboration among various specialties within a healthcare institution including prescribing physicians. Successful the antimicrobial stewardship programs (ASPs) should focus on collaboration between all healthcare professionals to shared knowledge and widespread diffusion of practice. Involvement of prescribing physicians in ASPs may rise their awareness on antimicrobial resistance. It is essential for an ASP to have at least one member who is an infectious diseases specialist. Pharmacists with advanced training or longstanding clinical experience in infectious diseases are also key actors for the design and implementation of the stewardship program interventions. In any healthcare setting, a significant amount of energy should be spent on infection prevention and control. Infection control specialists and hospital epidemiologists should be always included in the ASPs to coordinate efforts on monitoring and preventing healthcare-associated infections. Microbiologists should actively guide the proper use of tests and the flow of laboratory results. Being involved in providing surveillance data on antimicrobial resistance, they should provide periodic reports on antimicrobial resistance data allowing the multidisciplinary team to determine the ongoing burden of antimicrobial resistance in the hospital. Moreover, timely and accurate reporting of microbiology susceptibility test results allows selection of more appropriate targeted therapy, and may help reduce broad-spectrum antimicrobial use. Surgeons with adequate knowledge in surgical infections and surgical anatomy when involved in ASPs may audit antibiotic prescriptions, provide feedback to the prescribers and integrate best practices of antimicrobial use among surgeons, and act as champions among colleagues implementing change within their own sphere of influence. Infections are the main factors contributing to mortality in intensive care units (ICU). Intensivists have a critical role in treating multidrug resistant organisms in ICUs in critically ill patients. They have a crucial role in prescribing antimicrobial agents for the most challenging patients and are at the forefront of a successful ASP. Emergency departments (EDs) represent a particularly important setting for addressing inappropriate antimicrobial prescribing practices, given the frequent use of antibiotics in this setting that sits at the interface of the community and the hospital. Therefore, also ED practitioners should be involved in the ASPs. Without adequate support from hospital administration, the ASP will be inadequate or inconsistent since the programs do not generate revenue. Engagement of hospital administration has been confirmed as a key factor for both developing and sustaining an ASP. Finally, an essential participant in antimicrobial stewardship who has been often unrecognized and underutilized is the “staff nurse.” Although the role of staff nurses has not formally been recognized in guidelines for implementing and operating ASPs they perform numerous functions that are integral to successful antimicrobial stewardship. Nurses are antibiotic first responders, central communicators, as well as 24-hour monitors of patient status.

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