Concerns with Antibiotic Resistance

Learning Goals

• Familiarize yourself with the existing state of antibiotic-resistant microorganisms both nationally and internationally.
• Gain insights into the societal and medical factors that contribute to the rise of resistant microbes.
• Comprehend the biological pressures and mechanisms that facilitate the development of resistant bacterial strains.
• Differentiate between clinical indications of viral sinusitis and those of bacterial sinusitis.
• Identify the main bacterial strains typically found in cases of acute bacterial sinusitis.
• Understand the clinical effectiveness of various antibiotics in managing sinusitis.
• Review the overall occurrence of resistant variants among the most common bacteria involved in acute bacterial sinusitis.
• Acquaint yourself with the principles of antibiotic stewardship.
• Examine current guidelines for premedicating patients who have prosthetic joint replacements.
• Stay updated on the latest warnings and recommendations from the World Health Organization (WHO) concerning antimicrobial resistance (AMR).

Overview

For over half a century, antibiotics have played a crucial role in safely and effectively managing bacterial infections in humans and animals. Initially hailed as "wonder drugs," their extensive and often inappropriate use has led to the treatment of a wide range of symptoms and conditions, many of which exceed their intended efficacy. This is particularly evident in the United States, where antibiotics are frequently prescribed for viral infections, despite their ineffectiveness in these cases.
The societal demand for antibiotics has surged, often compelling physicians to acquiesce to patient requests. Individuals seeking medical care, whether for themselves or their children, tend to prioritize swift relief from their symptoms and a quick return to daily activities. Patients often express dissatisfaction when informed that their condition is a “self-limiting viral infection,” and may feel overlooked if only over-the-counter treatments are suggested for symptom relief. A survey conducted by the Massachusetts Department of Public Health revealed that the uptick in antibiotic prescriptions by primary care physicians largely stems from “patient requests for these agents and the physicians’ hope to keep patients satisfied with their office visit.”

The significant rise in antibiotic consumption is reflected in reports from the industry regarding antibiotic production in the United States. In 1954, approximately 2 million pounds of antibiotics were manufactured annually. By 2015, the Centers for Disease Control and Prevention (CDC) noted that this figure had escalated to 50 million pounds per year. The usage in agriculture is even more staggering: the United Nations Food and Agriculture Organization estimates that around 60,000 tons of antibiotics are applied to livestock each year, with projections for continual growth. Despite this substantial production, bacteria persist, evolving into stronger strains that resist treatment. Consequently, this situation has led to unpredictable treatment outcomes, heightened disease complications, and challenges in formulating standard prescribing practices for various illnesses.

In the dental field, it is not uncommon for practitioners to assess a patient for tooth pain, only to find no dental issues and subsequently refer them to a general physician or otolaryngologist for possible sinus infection treatment. Acute sinusitis can often resemble or cause toothache, positioning dental practitioners as key referral points for ENT evaluations. It is also frequent for a dental professional to learn during a follow-up appointment that the patient is still managing their sinusitis, often reporting multiple courses of different antibiotics prescribed for the condition.

The increasing issue of antibiotic-resistant bacteria is a critical concern and is primarily linked to the excessive use of prescribed antibiotics. The CDC estimates that office-based physicians in the United States write around 100 million antibiotic prescriptions each year, with an additional 35 million issued from emergency departments. Hospitals account for an estimated 190 million antibiotic regimens prescribed annually. Alarmingly, it is believed that about 50% of these prescriptions are unnecessary and wrongly given for viral infections, which do not respond to antibiotic treatment. This inappropriate use has led to the emergence of various antibiotic-resistant strains.

The rise of bacterial “superbugs” has become a significant public health crisis. Dr. Margaret Chan, the Director-General of the World Health Organization (WHO), has described the emergence of these resistant organisms in her statement titled “Superbugs: Why we need action now,” deeming it a “global public health emergency.” In response to the challenges posed by acute sinusitis diagnosis and treatment, several health agencies formed a collaborative commission called the Sinus and Allergy Health Partnership (SAHP). This task force includes members from the American Academy of Otolaryngology-Head and Neck Surgery (AAHANS), the American Rhinologic Society, the American Academy of Otolaryngic Allergy, the CDC, and the Food and Drug Administration (FDA). Together with various medical experts specializing in infectious diseases, microbiology, and clinical pharmacy, SAHP developed clinical guidelines to assist physicians in curbing the unnecessary prescription of antibiotics for viral sinus infections.

This course will delve into the findings of the SAHP, particularly since sinusitis often prompts dental evaluations due to associated tooth pain. Additionally, the course will explore the broader implications of antibiotic resistance as a pressing public health issue.

Identifying and Managing Sinusitis

The initial step taken by SAHP involved establishing clinical criteria to distinguish between viral and bacterial sinusitis. Sinusitis is technically defined as an inflammatory condition affecting the paranasal sinuses. Since this condition often follows nasal inflammation (rhinitis) and a viral upper respiratory infection, the term “acute bacterial rhinosinusitis” (ABRS) was adopted by AAHANS in 1997 to describe this type of infection.

ABRS is highly prevalent, impacting approximately 35 million individuals in the United States annually. It ranks as the fifth most common diagnosis for which antibiotics are prescribed. Alarmingly, in about half of these instances, antibiotics are issued for self-limiting viral infections. Furthermore, when a bacterial infection is indeed present, doctors may prescribe an inadequate or unsuitable antibiotic regimen, which can lead to the emergence of resistant bacterial strains.

To differentiate between viral and bacterial infections, SAHP examined the typical symptoms associated with upper respiratory infections (URIs) and identified several that are common to both types, including:

• Nasal discomfort
• Nasal discharge (mucous and/or purulence)
• Sneezing
• Nasal congestion
• Fever
• Pressure in the facial region
• Postnasal drip
• Headache
• Toothache

In their analysis, SAHP found that a physical examination of patients with upper respiratory infections often yields inconclusive results, as the immune response to viral and bacterial pathogens can appear nearly identical. Various diagnostic methods—such as x-rays, CT scans, MRI, ultrasound, rhinoscopy, and endoscopy—can be employed to identify inflammation, mucosal thickening, and discharge in the sinus. However, these methods do not effectively distinguish between viral and bacterial infections. The only definitive way to ascertain whether viral sinusitis has progressed to bacterial sinusitis is through repeated endoscopic cultures or sinus aspirations, but this process is invasive, inconvenient, and costly, making it infrequently performed except for immunocompromised patients.

SAHP identified that the primary diagnostic distinction between viral and bacterial infections lies in the duration and severity of symptoms. Consequently, they concluded that the patient’s medical history is the most reliable diagnostic tool to differentiate between these infections. Based on their review of literature and clinical data, SAHP established the following diagnostic recommendations:

• Only 2% of adult viral URIs transition into bacterial infections.
• The typical duration of viral sinusitis symptoms in adults is about 9 days.
• Approximately 60% of patients with URI symptoms persisting for 10 days or more test positive for bacterial infections as confirmed by sinus aspirations.
• A transition to bacterial infection is likely if symptoms worsen after 5 to 7 days.
• Antibiotic treatment is warranted when:
  • Symptoms last for 10 days or longer.
  • Symptoms deteriorate after 5 to 7 days.
  • Sinus aspiration indicates bacterial involvement.

Infective Agents in Sinusitis

Most cases of sinusitis are attributed to the following viral agents, for which antibiotic treatment is ineffective:

• Human rhinovirus (the most common causative agent)
• Influenza A
• Influenza B
• Parainfluenza virus
• Coronavirus
• Adenovirus
• Enterovirus

In instances of acute bacterial rhinosinusitis (ABRS), where prescription antibiotics are necessary, the three predominant bacterial agents involved are:

• Streptococcus pneumoniae: isolated in 20% to 40% of ABRS cases in adult patients.
• Haemophilus influenzae: isolated in 22% to 35% of ABRS cases in adult patients.
• Moraxella catarrhalis: commonly isolated in ABRS cases in children.

Understanding the predominant bacterial agents responsible for ABRS is crucial for physicians to prescribe antibiotics with the appropriate spectrum of efficacy aimed at eradicating these specific bacteria. More targeted antibiotic treatments are less likely to contribute to the emergence of antibiotic-resistant strains.
The following antibiotics are considered first-line treatments for ABRS:

• Beta-Lactams: This category includes penicillins and cephalosporins, which are preferred for initial therapy of ABRS. Their mechanism involves interfering with bacterial cell wall synthesis by binding to cell wall proteins, leading to increased permeability and bacterial cell death.
  • Amoxicillin: The most effective oral beta-lactam for treating S. pneumoniae. However, 40% of H. influenzae and 100% of M. catarrhalis produce a beta-lactamase enzyme that can degrade amoxicillin.
  • Amoxicillin/Clavulanate: Clavulanic acid is added to inhibit beta-lactamase, making amoxicillin effective against all three bacterial strains.
  • Cephalosporins: Cefpodoxime and cefuroxime are the most effective options in this category.
• Fluoroquinolones: These antibiotics interfere with the enzyme DNA-gyrase, facilitating DNA unwinding for replication. They are not recommended for initial therapy and are not approved for use in children.
  • Levofloxacin (Levaquin)
  • Gatifloxacin
  • Ciprofloxacin (Cipro)
• Macrolides and Azalides: These drugs inhibit RNA protein synthesis by binding to bacterial ribosomes. There has been a rise in reported resistance among S. pneumoniae and H. influenzae.
  • Erythromycin
  • Clarithromycin
• Lincosamides: These inhibit bacterial protein synthesis through ribosomal binding.
  • Clindamycin: Ineffective against H. influenzae and M. catarrhalis.
• Tetracyclines: These exert a bacteriostatic effect by inhibiting RNA protein synthesis through reversible ribosomal binding. Use is contraindicated in children aged 8 to 10 due to the risk of enamel discoloration from tetracycline staining.
  • Doxycycline: Limited effectiveness against H. influenzae.

Resistance Mechanisms Explained

ABRS is increasingly challenging to treat due to the emergence of antibiotic-resistant bacterial strains, which render antibiotics ineffective against the primary infective agents. The significant rise in penicillin-resistant Streptococcus pneumoniae strains in the United States has raised serious public health concerns over the last decade.
In 1998, two pivotal studies were conducted: the Alexander Project, which aimed to quantify the prevalence of penicillin-resistant strains of S. pneumoniae in respiratory tract isolates from office-based physicians, and a CDC study that sampled S. pneumoniae isolates from hospital patients nationwide. The findings from these studies were:

1998 Alexander Project (Strep pneumoniae):

• 16.1% penicillin intermediate resistant
• 28.6% penicillin fully resistant
• 32.5% macrolide fully resistant
• 10.8% clindamycin fully resistant
• 21.7% doxycycline fully resistant

1998 CDC Report (Strep pneumoniae):

• 10.5% penicillin intermediate resistant
• 13.9% penicillin fully resistant

These figures highlight that a significant proportion of bacteria involved in ABRS will not respond to traditional antibiotic regimens, complicating the development of standard prescribing guidelines.

Ongoing research is uncovering the mechanisms of resistance employed by these bacteria, which may help in developing new antimicrobial agents that can overcome these strategies. The specific mechanisms of resistance encountered in ABRS include:

• Inhibition: Certain bacteria produce enzymes that inactivate or degrade antibiotics before they can exert their effects. This explains the ineffectiveness of various beta-lactams and tetracyclines against ABRS. The bacterial enzyme beta-lactamase hydrolyzes the amide bonds in antibiotics, rendering them clinically inactive. To counter this, drugs like amoxicillin are combined with beta-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam, which allow the antibiotic to function effectively.
• Reduced Permeability: Most antibiotics require entry into the bacterial cell to effectively eliminate the microorganism. Hydrophilic antibiotics must be transported through the bacterial cell wall via water-facilitated porin channels or protein-facilitated transport channels. Alterations in these cellular transport pathways can impede effective antibiotic action.
• Efflux Pumps: Streptococcus pneumoniae employs specific cellular transport mechanisms (efflux pumps) that actively expel antibiotic molecules from the bacteria before they can exert their effects. This limits the antibiotics' access to the interior of the bacterial cell.
• Target Site Alteration: Some bacteria can produce cellular protein complexes that differ slightly in configuration, preventing antibiotics from binding effectively to the altered sites. These modifications can occur on the bacterial cell wall or ribosome binding sites, often serving as a defense against beta-lactam antibiotics.

In addition to these specific mechanisms, several general factors contribute to the development of antibiotic-resistant strains:

• Gene Mutation: Mutations in bacterial chromosomal material can result in structural changes that alter the molecular characteristics and actions of the bacteria.
• Genetic Acquisition: Bacteria can acquire resistance-conferring chromosomal material from other bacteria through horizontal gene transfer.
• Selective Pressures: The overuse of antibiotics fosters an environment where weaker bacterial strains are eliminated, allowing more resistant strains to survive and proliferate. This natural selection process varies across strains. For instance, Streptococcus pneumoniae has developed significant penicillin resistance over approximately 25 years, while Enterobacter species have become fluoroquinolone-resistant in under 10 years.
• Multiple Drug Resistance: Bacterial strains exhibiting resistance to one antibiotic are likely to develop resistance to others, complicating treatment strategies and promoting the emergence of "superbugs" that are only susceptible to last-resort antibiotics, such as vancomycin.

These mechanisms of resistance are continuously at play globally, with many sources of antibiotic exposure remaining hidden. A significant amount of antibiotics, including pesticides, are administered to livestock and crops, raising similar concerns as those in human healthcare regarding inappropriate prescribing and overuse.
In February 2017, the WHO issued its first-ever list of virulent bacteria for which new antibiotics are urgently needed to stimulate research and development. The WHO emphasized that relying solely on market forces would not suffice to develop the new antibiotics necessary to address public health needs.

Priority 1: Critical

• Acinetobacter, carbapenem-resistant (carbapenem is a “last-resort” antibiotic)
• Pseudomonas, carbapenem-resistant
• Enterobacteriaceae (Klebsiella, E. coli, Proteus), carbapenem-resistant (notably, Klebsiella pneumoniae is a common intestinal bacterium causing life-threatening infections and has become a major cause of hospital-acquired infections such as pneumonia and bloodstream infections, with some cases now reported as colistin-resistant and untreatable).

Priority 2: High

• Enterococcus faecium, vancomycin-resistant
• Staphylococcus aureus, methicillin-resistant, vancomycin-resistant (a common cause of severe infections in healthcare settings; patients with MRSA infections are 64% more likely to die than those with non-resistant infections)
• Helicobacter pylori, clarithromycin-resistant
• Campylobacter spp., fluoroquinolone-resistant
• Salmonellae, fluoroquinolone-resistant
• Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone-resistant (failures to respond to third-generation cephalosporins have been confirmed in at least 10 countries, including Austria, Australia, Canada, France, Japan, Norway, Slovenia, South Africa, Sweden, and the United Kingdom)

Priority 3: Medium

• Streptococcus pneumoniae, penicillin-resistant
• Haemophilus influenzae, ampicillin-resistant
• Shigella spp., fluoroquinolone-resistant

Strategies for Preventing Resistance Development

The clinical principles aimed at preventing the emergence of resistant bacterial strains have been acknowledged for several years. However, they were only recently formalized into specific recommendations. To address this issue, the Alliance for the Prudent Use of Antibiotics organized a Summit on Antimicrobial Resistance in September 1999 in San Francisco, California. This Summit, held alongside the 39th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy, called for action from health practitioners to combat this growing problem. During the Conference, an action plan was developed by primary care physicians and infectious disease specialists to assist community physicians in adapting their antibiotic prescribing habits. The Summit's call for action included the following strategies:

• Avoid catering to patient requests for unnecessary antibiotics.
• Provide education to patients (and their parents) on appropriate versus inappropriate antibiotic usage.
• Conduct tests to identify the specific pathogen involved.
• Opt for narrow-spectrum antibiotics whenever possible.
• Ensure the full course of antibiotic therapy is completed.
• Administer prophylactic antibiotics only when necessary. This is particularly crucial for dental practitioners who frequently encounter patients requesting unnecessary pre-medications that do not comply with the latest American Heart Association guidelines.
• Adhere to proper hygiene protocols, including thorough handwashing between patients to minimize the spread of infectious diseases. However, the Summit advised against using antimicrobial hand soaps and lotions, as these may contribute to the development of resistant microorganisms.
• Motivate patients to obtain appropriate vaccinations.
• Enhance resistance surveillance systems. Physicians should establish adequate reporting systems and community information bases to stay informed about the status of resistant strains in their communities, which will aid their prescribing practices.
• Use antibiotics wisely in non-human contexts, limiting inappropriate prescribing in agricultural and veterinary settings.
• Promote the development of new drugs.

The Global Landscape

In 2015, the World Health Organization (WHO) initiated the Global Antimicrobial Resistance Surveillance System (GLASS) to establish a comprehensive global action plan against emerging superbugs. WHO emphasized that monitoring antimicrobial resistance (AMR) serves as the “cornerstone for assessing the burden of AMR,” supporting local, national, and global strategies. GLASS facilitates the standardized collection and reporting of AMR data, leading to enhanced analysis and decision-making to combat this escalating threat. To further raise awareness, WHO designated 2017 as “The Year of Antibiotic Resistance,” recognizing the alarming potential of AMR to be even more lethal than cancer, potentially claiming up to 10 million lives annually and costing the global economy as much as $100 trillion by 2050. Without intervention, AMR will heighten the risks associated with all surgical procedures, including those in dentistry.

Beyond medical concerns, AMR poses a significant threat to sustainable food production across many nations. Antibiotics are extensively utilized to manage diseases in livestock to ensure high-quality food production, covering beef, dairy, pork, poultry, farm-raised fish, and even crops and fruits. In addition to treating diseases, antimicrobials are often employed as growth promoters for animals; however, bacteria, parasites, and fungi are developing AMR, risking crossover into the human population. Due to rampant overuse in agriculture, antibiotic residues and resistant organisms have become pervasive in soil, water, and air. The swift nature of modern transportation facilitates the rapid global spread of AMR, with WHO stating, “AMR knows no borders.”

Resistance to penicillin was first observed as early as 1940, just 12 years after its discovery, even before it became widely used during World War II. This did not raise alarms, as new classes of antibiotics continued to emerge. However, a significant challenge in combating resistant organisms is the absence of new antibiotic classes in the past three decades. Antibiotics are categorized based on their chemical structures and mechanisms for killing bacteria; prolonged use of older classes leads to increased bacterial adaptation and resistance. This stagnation in antibiotic innovation stems largely from inadequate economic incentives for their development. Most pharmaceutical companies have exited the antibiotic market, deeming the investment insufficiently profitable. The barriers, both legal and financial, to introducing a new antibiotic are considerable, with the estimated cost of research, development, and patient testing reaching around $1 billion per drug. Unfortunately, the return on investment for antibiotics is significantly lower compared to other drug types, as their market success is not based on repeat consumption. The highest returns come from drugs for chronic diseases, such as diabetes and cardiovascular issues, where patients require multiple doses over their lifetimes. In 1980, there were 36 pharmaceutical companies in the U.S. and Europe actively engaged in antibiotic development; today, only four remain: Novartis AG, Merck, GlaxoSmithKline, and Sanofi SA. Due to this lack of innovation, a May 2017 report from the Annals of Internal Medicine revealed that nearly no antibiotics approved by the FDA since 2010 have shown superior outcomes for patient survival or disability compared to older, less expensive alternatives. Drug companies are primarily focused on developing combination drugs that merge two older antibiotics into one prescription at a significantly higher cost, without offering improved efficacy. For instance, Merck’s Zerbaxa, which combines two antibiotic classes, costs $2,000 for a weeklong regimen, whereas the standard levofloxacin is only 67 cents, both demonstrating similar treatment success rates. Dr. William DeGrado, a professor of pharmaceutical chemistry at U.C. San Francisco Medical School, commented, “Forces outside of science and medicine have had disastrous consequences.” This situation arises as small biotech firms lack adequate funding for development and testing, while investors prioritize more lucrative drug markets over the long-term investments required for new antibiotics.

In response to this trend, legislation enacted in 2012 empowered the FDA to classify new antibiotics as “qualified infectious disease products,” granting them priority review for approval and eligibility for an additional five years of market exclusivity to enhance return on investment.

Another deterrent to new drug development stems from judicial and patent office perspectives on drugs derived from botanical and natural entities. Approximately 70% of new bacteria-fighting drugs introduced to the market since 1981 have been based on natural products. However, a 2014 U.S. Patent Office ruling rejected all patent applications based on natural products. Once, pharmaceutical companies scoured rainforests for botanical cures, but this pursuit has diminished since 2014, as the Patent Office will not issue profit-protecting patents for drugs deemed “natural.” Without patent protection, pharmaceutical companies and investors are hesitant to commit resources to a risky and expensive competition.

The GLASS program has successfully identified specific bacteria that have developed significant AMR, showing resistance to first, second, and third-line antibiotics. As a result, physicians are increasingly relying on antibiotics previously abandoned due to severe side effects, such as Colistin. In recent years, Colistin has been labeled a last-resort treatment for superbugs, but for some patients, even this drug proves ineffective. During a devastating superbug outbreak at Providence Alaska Medical Center in 2011, the bacterium Acinetobacter baumannii caused severe infections in 19 patients, resulting in six fatalities despite treatment with Colistin. Dr. Robert Clifford, a microbiologist at Walter Reed Army Institute, remarked, “It’s the worst of all possible worlds: a bacterium that is good at establishing infection, and it cannot be treated with antibiotics.” Currently, there is an alarming rise in multi-drug-resistant Gram-negative bacteria, such as Acinetobacter spp., implicated in pneumonia, meningitis, urinary tract infections, and poor wound healing. These Gram-negative bacteria are particularly challenging to treat due to their tough membrane structures that repel most drugs. Highlighting the severity of this issue, biochemist and antibiotic researcher Dr. Kim Lewis of Northwestern University stated, “We are losing the standoff with pathogens. Without antibiotics, essentially you do not have modern medicine.”

Stewardship

Antimicrobial resistance (AMR) to antibiotics is emerging as one of the most significant public health challenges of the 21st century. Tim Evans, the World Bank's senior director for health, nutrition, and population, stated, “The cost of inaction on AMR is too great; it needs to be addressed urgently and resolutely. If gone unchecked, an additional 28 million people will fall into poverty by 2050, and a century of medical progress will be reversed.”

Without addressing the issue of inappropriate prescribing, the proliferation of resistant bacterial strains will only escalate. The consequences include poor treatment outcomes, loss of productivity from work and school, the need for multiple drug regimens, increased morbidity, more hospitalizations, and longer hospital stays. Currently, the financial burden of AMR in the United States is estimated at $20 billion annually, with the WHO warning of a potential cost of $100 trillion by 2050.
New diagnostic and treatment guidelines will emerge, as both physicians and dentists must reevaluate infections historically deemed relatively benign, recognizing their potential for chronic or life-threatening consequences. This new era of antimicrobial therapy will necessitate a clear distinction between viral and bacterial infections and will emphasize targeted treatment regimens, improved delivery systems, and appropriate withholding of antibiotics.

Hospitals and health agencies are encouraging the implementation of "stewardship" programs aimed at reducing unnecessary antibiotic prescriptions and reserving critical drugs for last-resort situations. Dr. Julie Trivedi, a hospital epidemiologist, states, “Infectious Disease is not like cardiology, where the latest drug is the one you want to use. It’s about utilizing the standard available drugs before moving on to new ones.”

Beginning January 1, 2018, the Joint Commission, a non-profit agency accrediting U.S. healthcare facilities, mandated that all hospitals and nursing facilities implement stewardship programs. Additionally, the Centers for Medicare & Medicaid proposed a rule requiring hospitals participating in these programs to establish stewardship programs, following California's lead as the first state to enact such legislation in 2014. This September, the United Nations General Assembly will debate how best to address AMR—marking only the third occasion the U.N. has tackled a “communicable health issue,” following HIV and Ebola.

In dentistry, the CDC reports that dentists prescribe 10% of all antibiotics in the healthcare sector. In 2013, general dentists issued 24.5 million courses of antibiotics, with a prescribing rate of 77 prescriptions per 1,000 people. The most commonly prescribed antibiotics by general dentists include:

• Amoxicillin: 56.3%
• Clindamycin: 14.4%
• Penicillin V: 13.2%
• Cephalexin: 4.9%
• Azithromycin: 4.7%
• Augmentin, Ciprofloxacin, Erythromycin: each less than 3%

The American Association of Endodontists' Position Paper, “AAE Guidance on the Use of Systemic Antibiotics,” warns that up to 50% of all antibiotics are prescribed or used incorrectly. A significant concern regarding oral antibiotics is the risk of Clostridium difficile (C. diff) infections (CDI). C. diff was responsible for nearly half a million infections and approximately 29,000 deaths in the U.S. in 2011. Clindamycin, amoxicillin, and cephalosporins, commonly prescribed for endodontic infections, are frequently associated with CDI. Therefore, the judicious use of antibiotics is critical to protecting patient health and ensuring optimal clinical outcomes while adhering to the principle of “do no harm” to avoid unnecessary prescriptions that could jeopardize patient well-being.

In 2016, the American Dental Association (ADA) published a report outlining stewardship guidelines for dental antibiotic prescribing, aiming to promote the proper use of antibiotics, enhance patient outcomes, reduce costs, curb antibiotic resistance, and mitigate the spread of infections caused by multi-drug-resistant organisms. Key clinical guidelines include:

• Recognizing that systemic antibiotics are rarely effective in managing localized infections.
• Utilizing therapies such as incision and drainage, extraction, or endodontic treatment as initial steps in addressing most oral bacterial infections.
• Acknowledging that toxicity, allergy, side effects, and CDI risks can arise even with a single dose of antibiotics; thus, potential benefits must be weighed against risks.
• Avoiding antibiotic prescriptions for oral viral infections, fungal infections, or oral ulcerations due to trauma and aphthae.
• Steering clear of prescriptions based on historical practices, patient demand, or pressure from other healthcare professionals.
• Educating patients on the importance of taking antibiotics as prescribed, avoiding sharing medications, and refraining from saving unused antibiotics for future use.

Patient education is crucial in preventing antibiotic overuse. Healthcare professionals must inform patients about the ineffectiveness of antibiotics for viral infections. Patients also bear the responsibility of completing their full antibiotic courses and avoiding the retention of leftover medications for self-diagnosed infections. Collaboration with colleagues in veterinary and agricultural sciences is also essential to curtail the overuse of antibiotics in those fields.

Research indicates that physicians can modify their prescribing habits without negatively affecting patient treatment outcomes. A study involving primary care physicians in Denver, Colorado, revealed a 26% reduction in antibiotic prescribing rates for upper respiratory infections, with no increase in return visits for unresolved bronchitis or pneumonia.

Other countries are adopting similar programs. In Western Europe, common prescribing guidelines for pediatric ear infections recommend limiting antibiotic dispensing to cases where symptoms persist longer than 2-3 days or when frank drainage is present. Clinical trials demonstrate that supportive care with analgesics and antipyretics is as effective as antibiotics for resolving these infections. Evidence shows that treatment with acetaminophen or anti-inflammatory medications effectively alleviates discomfort and fever without the risk of promoting antibiotic resistance.

Dentists should pay close attention to the latest guidelines concerning antibiotic prophylaxis before invasive dental procedures for patients with prosthetic joint replacements (knee, hip, etc.). With approximately one million prosthetic knee and hip replacement surgeries performed annually in the U.S., and projections suggesting this number will reach four million by 2030, dental office schedules will increasingly feature patients with prosthetic joints. Dentists need to stay informed about the latest guidelines from the American Academy of Orthopedic Surgeons (AAOS) and the ADA regarding antibiotic premedication.

Over the past 25 years, the AAOS and ADA have released six statements on antibiotic premedication for patients with joint replacements. As research has enhanced understanding of the relationship between dental procedures, bacteremias, joint replacement infections, and antibiotic efficacy, there has been a significant shift in the approach to prescribing antibiotic regimens for these patients. Initially, pre-op and post-op doses were recommended to prevent joint infections following invasive dental procedures. However, current guidelines advocate withholding antibiotics except in rare cases involving immunocompromise, diabetes, or a history of prior joint infections. The AAOS and ADA assert that prophylactic antibiotics are generally not recommended before dental procedures to prevent prosthetic joint infections.

Research findings reveal that 95% of all prosthetic joint infections are caused by Staphylococcal bacteria, not oral Streptococcus viridans. These staphylococcal organisms do not originate from oral sources but rather from bacterial infections during orthopedic surgery or skin infections leading to subsequent blood infections. Additionally, the transient Strep bacteremia occurring after dental procedures is minimal compared to daily bacteremia from eating, brushing, and flossing.

Furthermore, studies have shown that antibiotic premedication is ineffective in preventing bacteremia associated with invasive dental procedures. A dose of 2 grams of Amoxicillin reduces less than 50% of the bacteremia from invasive dental procedures, and Clindamycin (for patients allergic to Amoxicillin) has proven to be no more effective than a placebo. These findings have fundamentally altered the risk/benefit assessment of prophylactic antibiotic regimens aimed at preventing prosthetic joint infections. The focus has shifted towards minimizing harm and protecting patients from the potential adverse effects of unnecessary antibiotics.

Risks associated with antibiotic use include allergic reactions, anaphylaxis, gastrointestinal disturbances, the emergence of antibiotic-resistant bacteria, and secondary infections such as Clostridioides difficile (C. diff). This increasingly significant concern is highlighted by recent CDC figures, which estimate approximately 500,000 C. diff infections in the U.S. annually. Additionally, one in six patients who contract a C. diff infection will experience a recurrent infection within 2-8 weeks, and one in eleven patients aged 65 or older who develop a healthcare-associated CDI will die within 30 days.

Given that most CDI cases occur in patients currently taking antibiotics or shortly after completing a course, dentists must be vigilant about the specific risk factors for secondary CDI when prescribing systemic antibiotics for dental infections.

Risk Factors for C. diff:

• Age 65 and older
• Recent hospitalization or care facility admission
• Immunocompromised status (weakened immune system, use of immunosuppressive medications, HIV/AIDS diagnosis)
• History of prior C. diff infection
• Recent antibiotic treatment

Typical Symptoms of C.diff:

• Fever
• Severe diarrhea
• Stomach pain or tenderness
• Colitis
• Nausea
• Loss of appetite

Treatment of CDI

The diagnosis of CDI begins with stool samples, followed by a 10-day treatment regimen of vancomycin or fidaxomicin, with some cases requiring hospital admission. For recurrent CDI, fecal microbiota transplants may be utilized to restore and rebalance the patient's gastrointestinal flora.

Each year, antibiotic-resistant infections result in approximately 35,000 deaths in the United States, with 29,000 fatalities specifically attributed to CDI. Most C. diff infections stem from antibiotic use, meaning unnecessary antibiotic prescriptions contribute significantly to these fatalities. The likelihood of experiencing adverse or life-threatening reactions increases with the number of antibiotic courses a patient receives. Given the average number of dental procedures patients undergo yearly, reducing antibiotic regimens prescribed is crucial.

To enhance patient safety, dentists must strictly limit antibiotic use for patients with prosthetic joint replacements, adhering to the guidelines established by the American Academy of Orthopedic Surgeons (AAOS) and the American Dental Association (ADA). As many orthopedic surgeons continue to prescribe antibiotic prophylaxis for their patients with prosthetic joints despite updated guidelines, it is vital for dentists to thoroughly inform their patients about current protocols and the supporting science. Dentists should encourage patients to discuss the necessity of antibiotics with their orthopedic surgeons, safeguarding their long-term health. Legal liability for adverse side effects stemming from unnecessary antibiotic prescriptions is anticipated to increase. If an orthopedic surgeon recommends antibiotic prophylaxis that contradicts AAOS and ADA guidelines, it has become standard protocol for the surgeon to prescribe the antibiotics and assume legal responsibility for any negative outcomes.

Promising Emerging Therapies

Recent advances in antibiotic development offer hope for effective alternatives to combat antibiotic resistance. Researchers at the University of California, Santa Barbara (UCSB), have published pivotal studies on diagnosing and treating antibiotic-resistant organisms.

UCSB scientists discovered that existing FDA-approved antibiotics can be employed more effectively through a new testing regimen that tailors prescriptions to individual patients. Traditionally, testing for antibiotic efficacy involved placing various antibiotic disks on Petri dishes inoculated with the patient’s bacteria and measuring the “kill zones” around each disk. The UCSB study, “Reevaluation of FDA-approved Antibiotics with Increased Diagnostic Accuracy for Assessment of Antimicrobial Resistance,” published in Cell Reports, emphasized the importance of considering the patient's internal environmental conditions that affect drug potency when selecting an antibiotic. This rigorous testing approach involved screening over 500 antibiotic-bacteria combinations, allowing the use of currently available FDA-approved antibiotics in customized regimens that are more potent and effective, potentially reducing the need for “last-resort” antibiotics. This approach also decreases cycles of antibiotic resistance by avoiding the prescription of multiple regimens when earlier treatments fail.

Another significant breakthrough at UCSB involved the development of a new antibiotic capable of eliminating bacterial “superbugs” without fostering bacterial resistance. The study, “A Broad-Spectrum Synthetic Antibiotic That Does Not Evoke Bacterial Resistance,” published in eBioMedicine, reported the creation of an innovative antibiotic that disrupts multiple bacterial functions simultaneously. As resistance remains a major barrier to developing new antibiotics, UCSB researchers successfully designed a drug that does not induce bacterial resistance. This new antibiotic targets the bacterial cell membrane through various mechanisms, resulting in broad-spectrum antibacterial activity. It is currently progressing through FDA clinical testing and represents a promising advancement in combating superbugs without promoting antibiotic resistance.

Summary

Preventing the rise of drug-resistant organisms requires action from every healthcare practitioner worldwide. Individual efforts in community-based offices, clinics, or hospitals can contribute to a multinational impact. This represents a practical application of the principles to “do no harm” and “think globally: act locally.”

Quiz For Concerns with Antibiotic Resistance