Antibiotic Stewardship: Common Questions and Facts

Key Takeaways:

• Antibiotic resistance, a global health threat, is not just a local concern. It’s a worldwide issue when bacteria develop the ability to survive the drugs designed to kill them. This can lead to severe infections that are difficult or impossible to treat, posing a significant challenge to healthcare systems globally.
• Antibiotic stewardship is the responsible use of antibiotics to prevent the development of antibiotic-resistant bacteria.
• Antibiotic stewardship program strategies are developing rapidly to maximize patient outcomes and improve cost efficiency.
• Proper antibiotic use involves selecting the right drug, dose, and duration of treatment.
• Blood tests play a crucial role in identifying bacterial infections and determining antibiotic susceptibility, particularly blood cultures.

Antibiotics

Antibiotics, with their life-saving potential, can kill or inhibit the growth of microorganisms, primarily bacteria. Some antibiotics can also eliminate other organisms, such as protozoa. A common misconception is that antibiotics are effective against viruses or fungi–they are not. The life-saving potential of antibiotics is a testament to their importance in modern medicine.

Antibiotics have a rich history that dates back thousands of years to ancient Egypt and Greece. These early civilizations harnessed the power of molds to treat infections, a practice that laid the foundation for modern antibiotic use. However, the misuse and overuse of antibiotics in recent times have led to the emergence of antibiotic resistance, a global health crisis.

Antibiotics revolutionized medical treatment in the 20th century, a testament to human ingenuity. Alexander Fleming’s groundbreaking discovery of modern-day penicillin in 1928 was pivotal in this journey. Penicillin’s life-saving benefits, particularly evident during wartime, marked a significant milestone in the history of medicine. This history underscores the importance of responsible antibiotic use to preserve their effectiveness.

Many patients now expect a prescription for antibiotics when they see their physician for what they believe is an infection. Until recently, most physicians have been happy to oblige with antibiotic treatment since most patients improve not only if the antibiotic works but also because of its potential anti-inflammatory effects.

However, antibiotics are not without risks. They can cause side effects such as allergic reactions and contribute to the development of antibiotic resistance. Patients may feel better by taking antibiotics for any illness, but the responsible use of antibiotics is a shared responsibility, a role we all play, to avoid these potential risks. It’s crucial to understand that the benefits of antibiotics should be weighed against these risks.

Antibiotic Resistance and Stewardship

The problem of antibiotic resistance is an inevitable consequence of microorganisms evolving by using clever genetic tricks to perpetuate their survival. This resistance poses a significant threat to public health, potentially rendering our most potent antibiotics ineffective. Antibiotic stewardship, a term referring to the responsible use of antibiotics to preserve their effectiveness and safeguard public health, is an ethic we all can contribute.

The judicious use of antibiotics involves a multidisciplinary approach. Pharmacists, physicians, nurses, and other healthcare professionals are pivotal in antibiotic stewardship. Their expertise and dedication are crucial in ensuring the responsible use of antibiotics.

However, the responsibility for antibiotic stewardship extends beyond healthcare professionals. The public also plays a significant role by understanding antibiotics’ limitations, following prescribed treatments, and not pressuring healthcare providers for unnecessary antibiotics. Each of us has the power to contribute to antibiotic stewardship, making a difference in the fight against antibiotic resistance.

Two main antibiotic stewardship program strategies, preauthorization/formulary restriction and prospective audit with feedback, are now employed in major medical centers. Preauthorization/formulary restriction controls the use of antibiotics by requiring healthcare providers to get approval before prescribing certain antibiotics. For example, a hospital may have a list of approved antibiotics that can be prescribed without preauthorization, while others require approval.

A prospective audit with feedback reviews how antibiotics are used and gives healthcare providers feedback on their prescribing practices, helping them make more informed decisions. Other strategies include education and guidelines for healthcare providers, public awareness campaigns, and research on new antibiotics and alternative treatments.

In the future, we can look forward to more advanced diagnostic tools, such as rapid point-of-care tests, that can quickly identify the type of infection and its antibiotic susceptibility. We may also see improved surveillance systems that can track the use of antibiotics and the development of resistance in real-time. These advancements promise more effective and targeted antibiotic use, giving us hope in the ongoing fight against antibiotic resistance and promoting responsible antibiotic use.

Blood Tests for Detecting Bacterial Infections in the Bloodstream

The clinical assessment of patients with suspected viable bacteria in the bloodstream poses challenges since the bacteria may be harmless and transient. Transient bacteremia can occur routinely after dental work, other minor medical procedures, or even from a simple cut on the skin, and it usually resolves without consequences.

On the other hand, bacteremia can also lead to severe infections that may be catastrophic, even resulting in sepsis and death. Often, the only recognizable signs are fever or a focal infection, such as an ear infection, but these signs may be unreliable.

The bacteremia workup is a mix of clinical assessment and objective measures since the significance of the patient’s history may be nonspecific. General appearance, vital signs, and other physical signs may help raise clinical suspicion, but they may also be undependable for a definitive diagnosis. Helpful laboratory studies include:

• Blood Cultures:
  
  Blood cultures are the criterion standard for diagnosing bacteremia. The process involves aseptically inoculating a blood sample into a blood culture bottle and incubating the sample in a laboratory to determine if any bacteria grow. This is done by creating an environment that is conducive to bacterial growth.Positive blood cultures show a single isolate of a known pathogenic bacteria. For example, if the blood culture shows only Staphylococcus aureus, a known pathogenic bacteria, it’s considered non-contaminated. However, it’s considered contaminated if the blood culture shows multiple isolates or a mixture of pathogenic and non-pathogenic bacteria. Blood cultures are life-saving procedures in our fight against bacterial infections, as they help identify the specific type of bacteria causing the infection and allow for antibiotic susceptibility testing (AST).

  Most blood culture results rely on the time it takes for a blood culture to become positive. This time is significant as it indicates the growth rate of the bacteria. True pathogens, the actual cause of the infection, grow faster than contaminants, usually within 24 hours. This means that if a blood culture becomes positive within 24 hours, it’s more likely that the patient has a bacterial infection. For example, the routine detection time for Streptococcus pneumonia is 11-15 hours, Salmonella species is 9-12 hours, and Neisseria meningitidis is 12-23 hours. This quick detection is crucial for timely and effective treatments.¹

  It is still being determined whether the number of colonies grown in blood cultures is clinically significant. Occult bacteremia involving pneumococcus, for example, may produce fewer colony-forming units than the focal disease. In the case of meningococcal infections, high colony-forming units indicate an increased risk of meningitis.

  Blood cultures help identify the specific type of bacteria causing the infection and allow antibiotic susceptibility testing (AST). AST is an in vitro measurement that determines the likelihood of a particular antibiotic successfully treating an infection caused by a specific organism. In other words, it helps determine which antibiotics will be effective against the bacteria causing the infection. This test guides antibiotic treatment, ensuring the most effective antibiotic is used.

  Contamination during blood specimen collection can lead to false-positive results. Proper skin disinfection and aseptic techniques are essential. Devices, such as closed-system blood culture collection devices, have been proven to reduce contamination, even achieving 0% blood culture contamination rates.

  Timing of blood sample collection about antibiotic administration can also impact results. Blood samples should be collected before antibiotics are given to avoid false-negative results. For therapeutic drug monitoring, samples should be collected at specific times after antibiotic administration or specific blood culture bottles may be used that help inactivate the antibiotic, allowing the inoculated organisms to grow out.

 

• White Blood Cell Count:
  
  An increased white blood cell count is consistent with an increased risk of occult bacteremia, particularly pneumococcal bacteremia. However, high white blood cell counts can be present in other infections, such as viral respiratory infections. Most febrile children with high white blood cell counts do not have a bacterial infection causing the illness.  Most physicians use the white blood cell count as a screening tool for bacterial infection. They compare the white blood cell count with other test results and the clinical picture. 

 

• Lactate Level:
  
  The Centers for Medicare and Medicaid Services (CMS) issued a protocol for treating sepsis in 2018, known as SEP-1. This multi-component 3—and 6-hour resuscitation treatment is for patients with a diagnosis of severe sepsis or septic shock.The SEP-1 bundle, a set of guidelines for treating sepsis, includes antibiotic administration, fluid bolus, blood cultures, lactate measurement, vasopressors for fluid-refractory hypotension, and a reevaluation of volume status.² The SEP-1 protocol is considered “all-or-none,” meaning that a physician must complete all components or the patient fails the protocol. This means that all components of the SEP-1 bundle are essential for effectively treating sepsis.

  Lactate levels are limited in usefulness for most patients in clinical diagnosis of sepsis. The complexity of sepsis and the treatment variability suggest that more research is needed.

 

• Procalcitonin (PCT):
  
  Procalcitonin (PCT) is a prohormone of calcitonin. PCT levels increase rapidly after bacterial endotoxins enter the bloodstream, faster than CRP (C-reactive protein) levels (see below), usually within 2 to 4 hours.  The pathophysiology of PCT levels during infection and inflammation remains unclear. PCT levels are low in viral infections, systemic lupus erythematosus (SLE), and Crohn’s disease but rise significantly in bacterial infections and superinfections. PCT levels can also be high as a result of significant tissue injuries, such as after major surgery, burns, motor vehicle accidents, or cardiogenic shock.  

  PCT levels may have only limited use in diagnosing bacteremia. However, they may help differentiate bacterial pneumonia from viral pneumonia and chronic obstructive pulmonary disease (COPD).

 

• C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), and Cytokines:
  
  CRP and ESR have been used for years in clinical practice but are not considered established screening tests for occult bacteremia. ESR and CRP were studied before the widespread use of the conjugate Hib vaccine and included patients with focal infections.¹ A comparison with the white blood cell count revealed better sensitivity, but ESR and CRP do not accurately predict sepsis, only inflammation.  Interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α) all increase in the serum and cerebrospinal fluid (CSF) in gram-negative and gram-positive sepsis; the levels increase with the severity of illness.1 These cytokines likely have marginal clinical use and are not recommended as routine screening laboratory studies for occult bacteremia. 

 

• Antibiotic Susceptibility Testing (AST) and Therapeutic Drug Monitoring (TDM):
  
  Antibiotic Susceptibility Testing (AST) identifies which antibiotics will effectively treat a specific bacterial infection and at what dose. AST aims to manage an individual’s health against deadly infections.  The disk diffusion method, developed in the 1950s by Bauer and Kirby, is the established gold standard for confirming bacterial susceptibility.³ The principles included isolating the bacterial colony, suspending it in growth media, standardizing through a turbidity test, and exposing bacteria to various antibiotics. AST aims to prevent ineffective antibiotics and reduce the risk of antibiotic resistance.  

  Since the 1980s, many other methods have been developed using automated technologies. Automation, simplicity, and compactness have revolutionized AST methods and improved results. 

  All AST methods provide quantitative information; some offer specific qualitative and effective antibiotic dosages, such as minimum inhibitory concentration, and formulate a profile of empiric therapy for specific clinical scenarios. Therapeutic drug monitoring (TDM) is helpful for a narrow therapeutic range of antibiotics. It ensures that the antibiotic concentration in the bloodstream is within the desired range for effectiveness and safety. 

 

• Antibiotic Resistance:
  
  Antibiotic resistance defines the need for antimicrobial stewardship programs. Bacteria develop the ability to survive and grow despite antibiotics. Bacteria not only circumvent therapies but also create tachyphylaxis–a phenomenon similar to tolerance, where the bacteria have a progressively decreased response to a given antibiotic dose. To ensure future generations survive, bacteria pass resistance genes amongst and across species for widespread dissemination of antibiotic resistance. Antibiotic resistance began to come to light in the 1950s with the initial development of penicillinase.⁴ Since then, we have had problems with a host of pathogens (ESKAPE) that, in many instances, all remaining treatments are suboptimal. These ESKAPE pathogens include Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, ESBL Enterobacter, and Escherichia coli.5 Notable examples of antibiotic-resistant bacteria include: 
  • Methicillin-resistant Staphylococcus aureus (MRSA) 
  • Vancomycin-resistant Enterococci (VRE) 
  • Carbapenem-resistant Enterobacteriaceae (CRE) 

  Antibiotic resistance is a global health threat that threatens the risk of treatment failure, prolonged illness, and death. It also creates direct and indirect costs, ranging from acquiring an antibiotic to all associated costs, such as adverse effects, increased length of stay, and superinfection.  

  The pipeline of new antibiotics remains finite. Alternative therapies, such as biologics that selectively target specific proteins in the immune system, are being actively investigated. These limitations emphasize the importance of antibiotic stewardship and infection prevention measures. 

 

• Antibiotic Stewardship Strategies:
  
  Globally, there is support for antibiotic stewardship. In the US, California was the first state to require it. Guidelines from the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) enforce two core strategies for antibiotic stewardship.^6,7 
  • Prospective audit and feedback 
  • Formulary restriction with preauthorization required for selected antibiotics 

  Clinical pharmacists and infectious disease physicians implement these measures to decrease the transfer of antibiotic resistance, thereby reducing the number of infections caused by resistant organisms. These flexible strategies can be applied to different institutions and unique situations to avoid disputes. Overall, antibiotic stewardship strategies improve clinical outcomes and decrease costs.

Interesting Facts:

• Antibiotic resistance is estimated to cause 10 million deaths annually by 2050 if left unchecked.
• The discovery of penicillin in 1928 revolutionized the treatment of bacterial infections.
• Some bacteria, such as Pseudomonas aeruginosa, can develop resistance to multiple antibiotics.
• The human gut contains a diverse community of bacteria known as the gut microbiome, which can be disrupted by antibiotic use.
• Over the next 5-10 years, antimicrobial stewardship programs are estimated to expand beyond major medical centers and involve community hospitals, with national, state, and local government mandates.
• It is likely that as antibiotics that are ‘restricted’ become more streamlined in use, there will be more focus on patient safety, education, and efficacy.

References:

¹Kuppermann N. (1999). Occult bacteremia in young febrile children. Pediatric clinics of North America, 46(6), 1073–1109. https://doi.org/10.1016/s0031-3955(05)70176-0 

²Sloan, S. N. B., Rodriguez, N., Seward, T., Sare, L., Moore, L., Stahl, G., Johnson, K., Goade, S., & Arnce, R. (2022). Compliance with SEP-1 guidelines is associated with improved outcomes for septic shock but not for severe sepsis. Journal of intensive medicine, 2(3), 167–172. https://doi.org/10.1016/j.jointm.2022.03.003 

³Bauer, A. W., Kirby, W. M., Sherris, J. C., & Turck, M. (1966). Antibiotic susceptibility testing by a standardized single disk method. American journal of clinical pathology, 45(4), 493–496. 

⁴MCCORMICK, M. H., MCGUIRE, J. M., PITTENGER, G. E., PITTENGER, R. C., & STARK, W. M. (1955). Vancomycin, a new antibiotic. I. Chemical and biologic properties. Antibiotics annual, 3, 606–611. 

⁵Spellberg B, Blaser M, Guidos RJ et al. Combating antimicrobial resistance: policy recommendations to save lives. Clin. Infect. Dis. 52(Suppl. 5), S397–S428 (2011).
• Policy recommendations from the Infectious Diseases Society of America for opposing bacterial resistance and describing the current state of bacterial resistance.  

⁶Dellit TH, Owens RC, McGowan JE Jr et al. Infectious diseases society of America and the society for healthcare epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin. Infect. Dis. 44(2), 159–177 (2007).
•• Guidelines from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America describing implementation of stewardship programs. 

⁷Drew RH, White R, MacDougall C, Hermsen ED, Owens RC Jr. Insights from the Society of infectious diseases pharmacists on antimicrobial stewardship guidelines from the Infectious diseases Society of America and the Society for healthcare epidemiology of America. Pharmacotherapy 29(5), 593–607 (2009).
•• Expansion of the Infectious diseases Society of America stewardship guidelines including collaboration, use of information technology and the training of infectious diseases pharmacists.